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Breast Anatomy and Development
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PHYSIOLOGY
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Menopause
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Berg JW. The significance of axillary node levels in the study of breast carcinoma. Cancer 1955;8:776.
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Stibbe EP. The internal mammary lymphatic glands. J Anat 1918;52:257.
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Handley RS, Thackray AC. Invasion of internal mammary lymph nodes in carcinoma of the breast. BMJ 1954;1:161.
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Urban JA, Marjani MA. Significance of internal mammary lymph node metastases in breast cancer. AJR Am J Roentgenol 1971;111:130.
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Rouviere H. Anatomie des lymphatiques de l’homme. Paris: Masson 1932.
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Breast Anatomy and Development
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PHYSIOLOGY
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Ege GN. Internal mammary lymphoscintigraphy. Radiology 1975;118:101.
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Thomas JM, Redding WH, Sloane JP. The spread of breast cancer: impor- tance of the intrathoracic lymphatic route and its relevance to treatment. Br J Cancer 1979;40:540.
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Osborne MP, Jeyasingh K, Jewkes RF, et al. The preoperative detection of internal mammary lymph node metastases in breast cancer. Br J Surg 1979;66:813.
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Moosman DA. Anatomy of the pectoral nerves and their preservation in modified mastectomy. Am J Surg 1980;139:883.
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Boontje AH. Axillary vein entrapment. Br J Surg 1979;66:331.
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Russo J, Russo IH. Development of human mammary gland. In: Neville MC, Daniel CW, eds. The mammary gland. New York: Plenum 1987:67.
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Russo J, Lynch H, Russo IH. Mammary gland architecture as a determin- ing factor in the susceptibility of the human breast to cancer. Breast J 2001;7:278.
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Dooley WC, Ljung BM, Veronesi U, et al. Ductal lavage for the detection of cellular atypia in women at high risk for breast cancer. J Natl Cancer Inst 2001;93:1624.
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Valdes EK, Boolbol SK, Cohen JM, et al. Clinical experience with mammary ductoscopy. Ann Surg Onc 29 Jul, 2006; Epub ahead of print.
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Love SM, Barsky SH. Anatomy of the nipple and breast ducts revisited.
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Stolier AJ, Wang J. Terminal duct lobular units are scarce in the nipple: implications for prophylactic nipple-sparing mastectomy. Ann Surg Oncol 2008;15:438.
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Vogel PM, Georgiade NG, Fetter BF, et al. The correlation of histologic changes in the human breast with the menstrual cycle. Am J Pathol 1981;104:23.
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Wittliff JL, Lewko WM, Park DC, et al. Hormones, receptors and breast cancer. In: McGuire WL, ed. Steroid binding proteins of mammary tissues and their clinical significance in breast cancer, vol. 10. New York: Raven 1978:327.
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Zeppa R. Vascular response of the breast to estrogen. J Clin Endocrinol Metab 1969;29:695.
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Masters JRW, Drije JO, Scanisbrook JJ. Cyclic variation of DNA synthesis in human breast epithelium. J Natl Cancer Inst 1977;58:1263.
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Meyer JS. Cell proliferation in normal breast ducts, fibroadenomas and other ductal hyperplasias measured by nuclear labeling with tritiated thy- midine. Hum Pathol 1977;8:67.
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Ferguson DJP, Anderson TJ. Morphological evaluation of cell turnover in relation to the menstrual cycle in the “resting” human breast. Br J Cancer 1981;44:177.
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Longacre TA, Bartow SA. A correlative morphologic study of human breast and endometrium in the menstrual cycle. Am J Surg Pathol 1986;10:382.
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Potter CS, Watson RJ, Williams GT, et al. The effect of age and menstrual cycle upon proliferative activity of the normal human breast. Br J Cancer 1988;58:163.
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Breast Anatomy and Development
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Going JJ, Anderson TJ, Battersby S, et al. Proliferative and secretory activ- ity in human breast during natural and artificial menstrual cycles. Am J Pathol 1988;130:193.
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Breast Anatomy and Development
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Soderqvist G, Isaksson E, Schowltz BV, et al. Proliferation of breast epi- thelial cells in healthy women during the menstrual cycle. Am J Obstet Gynecol 1997;176:123.
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Breast Anatomy and Development
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PHYSIOLOGY
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Laidlaw IJ, Clarke RB, Howell A, et al. The proliferation of normal human breast tissue implanted into athymic nude mice is stimulated by estrogen but not progesterone. Endocrinology 1995;136:164.
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C H A P T E R 2
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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Clinical Perspectives
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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Maria Ouzounova, Suling Liu, and Max S. Wicha
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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CHAPTER CONTENTS
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Identification of Normal Breast Stem Cells Breast Carcinogenesis
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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CHAPTER CONTENTS
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Isolation and Characterization of Breast Cancer Stem Cells BCSC Markers
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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CHAPTER CONTENTS
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Aldehyde Dehydrogenase 1
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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Lineage Tracing
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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CHAPTER CONTENTS
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Therapeutic Implications of Breast Cancer Stem Cells Notch Pathway
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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Hedgehog Pathway Other Pathways
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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CHAPTER CONTENTS
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There has been accumulating evidence for the existence of a subcomponent of cancer cells that have stem cell prop- erties and have been termed “cancer stem cells.” Although the concept that cancer originates from the transformation of “germ cells” or “stem cells” was first proposed over 150 years ago, it is only recently that advances in stem cell biol- ogy have allowed for a more direct testing of the cancer stem cell hypothesis. Stem cells are defined by their ability to undergo self-renewal, as well as multi-lineage differentia- tion. This self-renewal can be either asymmetric or sym- metric. Self-renewal is distinguished from other proliferative processes in that at least one of the progeny of self-renewal is identical to the initial stem cell. In all other replicative processes, the progeny of division undergo a series of dif- ferentiation events (1). In asymmetric stem cell self-renewal, one of the two progeny is identical to the initial stem cell, whereas the other cell is a committed progenitor cell, which undergoes cellular differentiation. Because the product of an asymmetric self-renewal division is one stem cell and one dif- ferentiated cell, this process maintains stem cell numbers. In contrast, symmetric self-renewal results in the production of two stem cells; by its very nature this results in stem cell expansion. Although stem cells themselves are slowly divid- ing, progenitor cells derived from them are highly prolifera- tive (2). This expanding progenitor cell also has the ability to differentiate into the lineages comprising the adult tissue. Embryonic stem cells are pluripotent, able to differentiate into all derivatives of the three primary germ layers (ecto- derm, endoderm, and mesoderm), whereas adult stem cells are multipotent, able to form all of the cell types that are found in the mature tissue of an organ. In the mammary gland, these differentiating cells generate three lineages: ductal epithelial cells, which line ducts; alveolar epithelial cells, which are the milk-producing cells; and myoepithelial cells, which are contractile cells lining ducts and alveoli.
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Based on this definition, cancer stem cells retain key stem cell properties. These properties include self-renewal, which initiates and drives tumorigenesis, and differentia- tion, albeit aberrant, which contributes to cellular hetero- geneity (3)
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CHAPTER CONTENTS
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In breast cancer, the discovery of tumor cells that dis- play stem cell properties provides a possible explanation as to why cancer may be so difficult to eradicate, as well as suggesting strategies for the targeting of this cell popu- lation. This chapter will examine the implications of the cancer stem cell hypothesis and enable an understanding of carcinogenesis, as well as its implications for develop- ing new strategies for prevention and therapy of breast cancer.
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IDENTIFICATION OF NORMAL BREAST STEM CELLS
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The existence of adult mammary stem cells was established nearly 50 years ago when DeOme et al. (4) observed that tissue fragments of epithelium isolated from several differ- ent regions of the mammary gland were able to reconstitute the entire mammary ductal tree upon transplantation. Later, serial transplantation experiments by Charles Daniel and colleagues (5) demonstrated that stem cells exist through- out the life span of the mouse. Further studies by Smith and Medina (6) suggested that mammary stem cells were present in all portions of the ductal mammary tree at all developmental stages. In 2006, two complementary studies demonstrated that a single cell from either the CD24lo (heat- stable antigen)/ CD29hi (1-integrin) (7) or CD24lo/CD49fhi (6-integrin) (8) epithelial population isolated from an adult virgin mouse could generate a functional mammary gland when transplanted into the cleared fat pad of recipient mice.
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15
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IDENTIFICATION OF NORMAL BREAST STEM CELLS
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Further analysis of the CD24loCD29hi cells revealed that this was a basal population of cells that was ER-negative (9). Limiting dilution transplantation experiments by Smalley and co-workers (10) illustrated that CD24lo ER-negative basal cells displayed the highest stem cell activity (as defined by mammary repopulating units), whereas ER- positive luminal cells exhibited very little stem cell activity. Conversely, Booth and Smith (11) suggested that long-lived, slow-dividing, label-retaining ER-positive cells comprise a progenitor cell population that can directly respond to hormones. The relationship of these cells characterized in situ to the CD24lo cells identified by fluorescence acti- vated cell sorting remains to be established. A well-estab- lished in vitro system for assays of stem cell behavior—the mammospheres culture system—is a nonadherent assay in which mammary stem cells are cultured as floating cell colo- nies, without inducing cell differentiation. It was shown that human breast epithelial cells formed mammospheres after 7 to 10 days of culture, which maintained a primitive phe- notype and therefore did not express markers associated with terminal differentiation (12,13). In culture conditions which favored cell differentiation, cells isolated from disso- ciated mammospheres were shown to have the capacity for multi-lineage differentiation in two dimensional culture (as assessed by expression of cell-type specific markers) and in three-dimensional culture gave rise to lobular-alveolar structures (12).
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IDENTIFICATION OF NORMAL BREAST STEM CELLS
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Ginestier et al. (14) have described the expression of aldehyde dehydrogenase 1 (ALDH1) as a stem cell marker that can be utilized to isolate human mammary stem cells. ALDH1 is a detoxifying enzyme responsible for the oxida- tion of intracellular aldehydes. This enzyme may play a role in early differentiation of stem cells through its role in oxidizing retinol to retinoic acid (15). It is expressed in hematopoietic and neuronal stem and progenitor cells and can be detected utilizing an enzymatic assay (ALDEFLUOR; Aldagen, Durham, North Carolina) (16). Human mammary epithelial cells with a high enzymatic activity for ALDH (ALDEFLUOR positive), isolated from reduction mammo- plasties, were able to reconstitute human mammary gland structures when implanted in the humanized fat pad of NOD/SCID mice. Using ALDH1 antibody to immunostain paraffin-embedded sections of human normal breast epi- thelium researchers identified a relatively rare population of ALDH1-positive cells located in the terminal ductal lobu- lar units (TDLUs). ALDH1-positive cells appeared to form a bridge in the lumen that was located at the bifurcation point of side branches in the TDLUs (14). This is consistent with recently published data demonstrating that human stem/ progenitor cells are localized in the ductal part of the TDLU structures (17).
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IDENTIFICATION OF NORMAL BREAST STEM CELLS
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The identification of mammary stem cell markers and
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IDENTIFICATION OF NORMAL BREAST STEM CELLS
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the development of in vitro and murine models utilizing these cells should facilitate the study of adult breast stem cells to elucidate their role in mammary development. Furthermore, defining the pathways that regulate mammary stem cell self-renewal and differentiation should shed light on events involved in breast carcinogenesis.
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BREAST CARCINOGENESIS
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Traditionally, cancer has been considered as a multistep process defined by the sequential mutation of key genes driving the uncontrolled clonal expansion of a cell. However, important recent progress in basic research has challenged these concepts at different levels. First, the role of the tumor microenvironment is now well recognized, including
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BREAST CARCINOGENESIS
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the interaction with the extracellular matrix (ECM) and the immune system (18,19). Indeed, epithelial cells are depen- dent on interactions with specific components of the ECM for survival, proliferation, and differentiation. In addition, the initial steps in tumor establishment are associated with a deficiency in the mechanisms of immunosurveillance. Second, the role of epigenetic deregulation, as opposed to genetic aberrations, in most human tumors is becom- ing increasingly evident. Epigenetic mechanisms appear to play a fundamental role in cancer establishment and progression, and their deregulation has been reported at multiple levels, including DNA methylation, histone modifi- cations, and microRNA expression (20–24). Third, a “cancer stem cell” model of tumorigenesis has gained experimental support. This model suggests that tumors are sustained in their pathological growth by a small subpopulation of tumor cells with “stem-like” properties, in a way analogous to nor- mal organogenesis. Cancer stem cell (CSC) is an operational term to functionally define this distinct subpopulation of tumor cells with deregulated potential for self-renewal, excessive proliferation, and aberrant differentiation into heterogeneous progeny, generating intratumor heterogene- ity (25,26) Indeed, classical models of carcinogenesis can be described as “stochastic” or “random,” in which any cell in an organ, such as the breast, can be transformed by the right combination of mutations (27). As a result, all or most of the cells in a fully developed cancer are equally malignant (Fig. 2-1). It follows that strategies designed to treat and ultimately cure these cancers require the killing of all these malignant cells. Conversely, the cancer stem cell hypothesis is a fundamentally different model composed of two separate, but interrelated components. The first is that tumors originate in tissue stem and/or progenitor cells through the deregulation of the normally tightly regulated process of self-renewal (28). As a consequence, it is believed that tumors contain a cellular component that retains key stem cell properties including self-renewal, which initi- ates and drives carcinogenesis and differentiation, albeit aberrant, that contributes to tumor cellular heterogeneity (Fig. 2-1B) (29). However, it is important to emphasize that the CSC and stochastic model of carcinogenesis are not mutually exclusive and probably both mechanisms contrib- ute to tumor heterogeneity. As a result tumors may be con- stituted by multiple CSC clones which evolve during tumor development and treatment.
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ISOLATION AND CHARACTERIZATION
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OF BREAST CANCER STEM CELLS
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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ISOLATION AND CHARACTERIZATION
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Even though important progress has been made, the isola- tion and characterization of cancer stem cells remains a challenge. In order to validate the method selected as an appropriate technique to isolate cancer stem cells, it is crucial to use assays that can assess the stem cell proper- ties of self-renewal and differentiation. Presently, the gold standard for identifying breast cancer stem cell activity is the xenograft model based on the orthotopic injection of human breast cancer cells into the humanized clear mammary fat pad of immunodeficient mice. The cancer stem cell population is characterized by enhanced tumori- genicity and is able to regenerate the tumor upon serial passage, whereas the tumor cell population depleted of cancer stem cells cannot sustain tumor growth upon serial transformation (Fig. 2-2). In addition to self-renewal, cancer stem cells retain the ability to differentiate, albeit abnormally, generating non–self-renewing cell popula- tions that constitute the bulk of a tumor. Development
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A B FIGURE 2-1 Two Models of Breast Carcinogenesis. A: According to the sto- chastic model any mam- mary epithelial cell can be transformed by the right
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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ISOLATION AND CHARACTERIZATION
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Normal breast epithelium
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ISOLATION AND CHARACTERIZATION
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Malignant breast epithelium
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ISOLATION AND CHARACTERIZATION
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combination of mutations and resultant cancer cells of different phenotypes have extensive proliferation
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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ISOLATION AND CHARACTERIZATION
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potential. B: According to the stem cell hierarchical model, cancers originate from the malignant transformation
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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ISOLATION AND CHARACTERIZATION
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of a normal breast stem/ progenitor cell. Most can- cer cells have only limited proliferative potential, but cancer stem cells that have self-renewal capacity drive tumorigenesis.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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ISOLATION AND CHARACTERIZATION
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Ductal epithelial cell
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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ISOLATION AND CHARACTERIZATION
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Breast cancer stem cell Breast cancer cell
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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ISOLATION AND CHARACTERIZATION
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Myoepithelial cell Adult stem/progenitor cell
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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ISOLATION AND CHARACTERIZATION
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Malignant transformations
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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ISOLATION AND CHARACTERIZATION
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of in vitro assays such as the mammosphere assay has been also used for enrichment of cancer stem cell popula- tion. This method is a nonadherent colony forming assay developed by Dontu et al. (30) where only cells with self- renewal capacity are able to survive and grow in anchor- age-independent conditions while differentiated cells will undergo anoikis.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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ISOLATION AND CHARACTERIZATION
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In summary, several different techniques have been uti- lized to enrich for and identify breast cancer stem cells. The in vitro cancer stem cell assays provide an important tool for mechanistic studies as well as for screening of specific drugs targeting this population. However, at this time, self-renewal can only be confirmed by serial passage in xenograft mod- els. A potential limitation of these systems relates to the microenvironmental difference found in humans compared to NOD/SCID mice (31). Another important characteristic of both in vivo and in vitro assays to be taken into account is that these techniques may only detect proliferating stem cells but not dormant cancer stem cells.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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BCSC MARKERS
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The first evidence for the existence of cancer stem cells in human solid tumors came from the study of Al-Hajj et al.
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BCSC MARKERS
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(32) where they utilized techniques based on seminal stud- ies identifying leukemic stem cells by Bonnet and Dick (33). Utilizing cell surface markers and flow cytometry, these authors isolated a tumorigenic population of cells in human breast cancer that displayed cancer stem cell properties. This population was defined by the expression of cell sur- face markers (CD44+/CD24–/low/lin). When injected in the mammary fat pad of NOD/SCID mice as few as 200 of these cells were able to form tumors, whereas 20,000 cells that
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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BCSC MARKERS
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did not display this phenotype failed to generate tumors. Tumors that formed in mice recapitulated the phenotypic heterogeneity of the initial tumor. The ability to serially transplant the tumors from an enriched stem cell population provides strong support for the existence of stem cells in breast cancers. CD44 appears to be also expressed in cancer stem cells in other tumor types including colon, pancreas, prostate, and head and neck (34–37).
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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BCSC MARKERS
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Recently it has been suggested that expression of the cell surface markers EpCAM and CD49f can be used to define functional populations of normal mouse and human mammary cells. Based on in vitro and mouse fat pad re-implantation studies it has been suggested that EpCAM CD49f+ cells represent mammary stem cells, EpCAM+CD49+ (double-positive cells): luminal progenitors; EpCAM+CD49f–: differentiated luminal cells; and EpCAMCD49f: stromal cells. However, double positive (EpCAM+CD49f+) so-called luminal progenitor cells, have been found to give rise to basal as well as luminal cells when cultured in vitro. These results suggest that in addition to luminal progenitors, the EpCAM+CD49f+ population may also contain a sub-popula- tion with stem cell characteristics. A recent study in tri- ple negative breast cancer demonstrated the existence of two different subpopulations based on CD49f expression: CD49f quiescent cells and CD49f+ cells. CD49f quiescent cells present high tumor-initiating potential as compared to CD49f+ cells. Gene expression analysis reveals that CD49f quiescent cells overexpress epithelial-to-mesenchymal transition-driving genes, reminiscent of tumor-initiating cells and claudin-low breast cancer (38). Emerging stud- ies suggest that while CD49f+/EpCAM and CD44+/CD24 cells may represent the EMT-like CSC phenotype, ALDH+ cells may represent the MET-like CSC phenotype. These two CSC states may be interconvertible. EMT-like CSCs
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BCSC MARKERS
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Xenotransplantation B Cancer stem cell isolation
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BCSC MARKERS
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FIGURE 2-2 Isolation and characterization of breast cancer stem cells. A: The xeno- graft model involves introduction of tumor cells into the cleared fat pad of not otherwise specified/severe combined immunodeficiency (NOD/SCID) mice that have been human- ized by the introduction of human mammary fibroblasts. B: When the xenograft is estab- lished, breast cancer stem cells can be separated from the rest of the tumor cells utilizing different techniques such as the ALDEFLUOR (Aldagen, Durham, North Carolina) assay.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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BCSC MARKERS
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C: When transplanted, the cancer stem cell population initiates and maintains tumor growth upon serial passage, whereas the tumor cell population depleted of the cancer stem cell population fails to generate tumors D.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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BCSC MARKERS
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have a mesenchymal morphology, are largely quiescent, invasive, and characterized by expression of the CSC mark- ers CD24CD44+ and are EpCAMCD49f+. In contrast, the MET (mesenchymal epithelial transition) state of CSCs is characterized by active self-renewal and expression of the CSC markers ALDH and EpCAM+CD49f+. A subpopulation of cells expressing both CD24CD44+ and ALDH may represent cells in transition between these states. This transition is regulated by signals originating in the microenvironment that could be a potential therapeutic target.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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ALDEHYDE DEHYDROGENASE 1
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ALDH enzymatic activity has been recently used to isolate normal human breast stem and progenitors cells (14). The authors demonstrated that ALDEFLUOR-positive cells iso- lated from human breast cancer display properties of can- cer stem cells shown by the ability of these cells, but not ALDEFLUOR-negative cells, to generate tumors in NOD/SCID mice. Serial passages of the ALDEFLUOR-positive cells gener- ate tumors that recapitulated the phenotypic heterogeneity
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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ALDEHYDE DEHYDROGENASE 1
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of the initial tumor. Interestingly, the ALDEFLUOR-positive cell population detected in breast tumors has a small overlap with the previously described cancer stem cell, CD44+/CD24/lin phenotype (32). In the tumors investigated, the overlap rep- resented approximately 1% or less of the total cancer cell population. The ALDEFLUOR-positive CD44+/CD24/lin cells appeared to be highly enriched in tumorigenic capability, being able to generate tumors from as few as 20 cells. ALDH1 immunostaining of paraffin-embedded specimens was utilized to identify breast cancer stem cells in situ. Analysis of ALDH1 expression in 577 human breast carcinomas showed that this stem or progenitor cell marker is a powerful predictor of poor clinical outcome and correlates with tumor histological grade, ER and PR negativity, proliferation index as assessed by Ki-67 expression, and ERBB2 overexpression.
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LINEAGE TRACING
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Recent studies utilizing mouse models of glioblastoma, skin and intestinal tumors provide important validation of the cancer stem cell model (39–41). These studies provide the first evidence that CSC arise de novo during tumor develop- ment in intact organs. Lineage tracing methods take advan- tage of fluorescent marking of stem cells and their progeny allowing for the visualization and monitoring of cancer stem cells. Chen et al. and Driessens et al., together with Schepers et al., traced individual cells in intact tumors and demonstrated that cancer cells are organized hierarchically. Using lineage tracing Driessens et al. observed that the cells present an important variability in proliferation poten- tial with only 20% able to generate daughter cells capable of tumor regeneration. Moreover, the studies of Chen et al. suggested that targeting both CSC and their progeny improved therapeutic outcome in vivo. These studies raise the issue of a possible evolutionary competition between non-stem cells and stem cells within the tumor, with the non-stem cells presence representing a brake for the tumor
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LINEAGE TRACING
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development. In accordance with this idea Driessens et al. observed enrichment of the CSC population and a concomi- tant decrease in the non-stem cell population during cancer progression. Together these results suggest that prevention of the increase in the stem-like compartment would retard tumor progression.
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THERAPEUTIC IMPLICATIONS OF BREAST CANCER STEM CELLS
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Although advances have been made in the treatment of localized breast cancer, there has been less progress in the treatment of advanced metastatic disease. Some of this lack of progress may be due to the failure of current therapies to target cancer stem cells (Fig. 2-3). The cancer stem cell hypothesis has important implications for the develop- ment of cancer therapeutics. Recent evidence indicates that breast CSC (42) as well as CSC from other tumor types, are relatively resistant to both radiation and chemotherapy (43). There are several postulated mechanisms for this resistance. Stem cells proliferate slowly; they are largely in the G0 phase of the cell cycle for extended periods of time, making them resistant to cell-cycle–dependent chemotherapeutic agents. In addition, CSC expressed increased adenosine triphos- phate–binding cassette proteins known to efflux chemother- apeutic drugs. Indeed, ABCG2, or breast cancer–resistance protein, was initially identified in breast cancers. This mol- ecule is overexpressed in stem cells and has been utilized to purify breast and other stem cells by exclusion of Hoechst dye, generating the so-called side population detected by flow cytometry (44). In addition, enzymes such as ALDH that are highly expressed in stem cells are able to metabolize chemotherapeutic agents such as cyclophosphamide (45).
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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THERAPEUTIC IMPLICATIONS OF BREAST CANCER STEM CELLS
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CSC may also express increased levels of antiapoptotic
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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THERAPEUTIC IMPLICATIONS OF BREAST CANCER STEM CELLS
| null | null |
molecules such as survivin and BCL2-family proteins (46). Current clinical trial designs have largely been based on
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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THERAPEUTIC IMPLICATIONS OF BREAST CANCER STEM CELLS
| null | null |
FIGURE 2-3 Therapeutic implications of breast cancer stem cells. Current therapies may shrink tumors by killing cells forming the tumor bulk. Because cancer stem cells are less sensitive to these therapies, they remain viable after therapy and re-establish the tumor. In contrast, therapies that target the cancer stem cell population limit tumor growth. Thus, even if cancer stem cell–directed therapies do not shrink tumors initially, they may eventually lead to cures. Furthermore, there is increasing evidence that cancer stem cells may play an important role in mediating tumor metastasis. The development of therapies targeting the cancer stem cell population may provide new opportunities to target metastatic disease.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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THERAPEUTIC IMPLICATIONS OF BREAST CANCER STEM CELLS
| null | null |
strategies aimed at producing tumor regression. Indeed, the Response Evaluation Criteria in Solid Tumors (RECIST) cri- teria measuring tumor response have been utilized to assess the efficacy of new therapeutic agents (47).
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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THERAPEUTIC IMPLICATIONS OF BREAST CANCER STEM CELLS
| null | null |
However, in breast cancer, as is the case with other malignancies, tumor regression does not correlate well with patient survival (48). In the neoadjuvant setting, only a com- plete pathologic response correlates with recurrence and survival, whereas partial response does not (49). Together with studies demonstrating resistance of breast CSC to che- motherapy and radiation therapy, these studies suggest that the limitations of present therapies may relate to their inabil- ity to target the cancer stem cell component. Recent neoad- juvant studies demonstrating an increase in the proportion of CD44+/CD24 breast CSC after chemotherapy suggest that this is the case (50,51). Furthermore, Korkaya et al. (52) have recently found that ERBB2 overexpression in normal human mammary epithelial cells as well as mammary carcinomas increases the proportion of stem cells as indicated by ALDH1 expression. The clinical relevance of this was demonstrated in a recent neoadjuvant breast cancer trial. Tumor regres- sion induced by neoadjuvant chemotherapy was associated with an increase in CD44+/CD24 cancer stem cells in residual tumors. In contrast, breast cancers with ERBB2 amplification had an increased proportion of CD44+/CD24 cells before treatment that was reduced by administration of the ERBB2 inhibitor lapatinib (53). Moreover Magnifico and colleagues used several HER2-overexpressing breast cancer cell lines to show an important role for HER2 in maintaining the cancer stem cell population. They show that within each cell line, cells displaying stem cell properties such as sphere forma- tion or increased aldehyde dehydrogenase expression also have increased HER2 expression compared with the bulk cell population. Furthermore, they show that the HER2 inhibitor trastuzumab or the combined HER2 and epidermal growth factor inhibitor lapatinib are able to specifically target this HER2-overexpressing cancer stem cell population (54). Using breast cancer cell lines, mouse xenograft models, and matched human primary and metastatic tissues, Ithimakin et al. (55) show that HER2 is selectively expressed in, and regulates self-renewal of, the cancer stem cell population in estrogen receptor-positive (ER+), HER2− luminal breast can- cers. Although trastuzumab had no effects on the growth of established luminal breast cancer mouse xenografts, admin- istration after tumor inoculation blocked subsequent tumor growth. HER2 expression is increased in luminal tumors grown in mouse bone xenografts, as well as in bone metas- tases from patients with breast cancer as compared with matched primary tumors. Furthermore, this increase in HER2 protein expression was not due to gene amplification but rather was mediated by receptor activator of NF-B (RANK)- ligand in the bone microenvironment. These studies suggest that the clinical efficacy of adjuvant trastuzumab may relate to the ability of this agent to target the CSC population in a process that does not require HER2 gene amplification.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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THERAPEUTIC IMPLICATIONS OF BREAST CANCER STEM CELLS
| null | null |
The clinical efficiency of ERBB2 inhibitors provides evi- dence for the effectiveness of agents capable of targeting breast cancer stem cells. In addition, elucidation of other pathways that regulate breast cancer stem cells, such as Notch and Hedgehog may provide new targets for therapeu- tic development.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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NOTCH PATHWAY
| null | null |
In mammals, there are four Notch receptors (Notch1 to Notch4), which interact with surface bound or secreted ligands (Delta-like 1, Delta-like 3, Delta-like 4, Jagged 1 and
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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NOTCH PATHWAY
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Jagged 2). Upon ligand binding, Notch receptors are acti- vated by serial cleavage events involving members of the ADAM protease family followed by intramembranous cleav- age regulated by -secretase (presenilin). Following proteo- lytic cleavage, the intracellular domain of Notch translocates to the nucleus to act on downstream targets such as the Hes and Hey transcription factors. Evidence for the role of Notch signaling in mammary development has been provided by transgenic models. The Notch pathway has been shown to play an important role in mammary carcinogenesis. Stimulation of Notch signaling resulted in a 10-fold increase in the number of secondary mammospheres obtained after dissociation of the primary spheres and Notch activation acts as a regulator of asymmetric cell fate decisions by pro- moting mammary self-renewal (56). Since -secretase is nec- essary for Notch processing -secretase inhibitors are able to inhibit Notch signaling. These results suggest that Notch is required for CSC expansion. Another study demonstrated dif- ferent targeted subpopulations for Notch1 and Notch4 (57). Notch4 inhibition in EpCAM+/CD44+/CD24lo subpopulation decreased sphere formation efficiency in vitro and abrogated tumor formation in vivo, while down regulation of Notch1 resulted in decreased tumor growth and rate. These data suggest a role of Notch4 in CSC maintenance and initiation, and a role of Notch1 in tumor proliferation. A relationship between Notch and HER2 signaling has been suggested by the demonstration that the HER2 promoter contains Notch- binding sequences. In addition, tumor cells derived from HER2 transgenic mice cultured in vitro in the presence of a
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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NOTCH PATHWAY
| null | null |
-secretase inhibitor form spheres at lower efficiency com- pared to untreated cells (58). These studies show important interactions between the Notch and HER2 pathways, both of which are involved in the regulation of cancer stem cells. As in the previously discussed studies, it was shown that lapatinib was able to reduce the cancer stem cell population following neoadjuvant chemotherapy. In metastatic disease, the clinical end points of tumor regression or time to tumor progression may reflect changes in bulk cell populations. The efficacy of trastuzumab or lapatinib in this setting may reflect the overexpression of HER2 in both cancer stem cells and bulk cell populations. In contrast, in the adjuvant set- ting, tumor recurrence may be driven by the cancer stem cell compartment. This compartment in turn may be driven by pathways such as Notch that do not depend on HER2 ampli- fication. This could explain the benefit of HER2 inhibition in the adjuvant setting in patients whose tumors do not display HER2 amplification suggested by retrospective analysis of trastuzumab adjuvant clinical trials. It would be interesting to determine whether these tumors display Notch activa- tion, which has been reported to occur in as many as 40% of human breast cancers (59). In these patients, inhibition of Notch signaling in addition to HER2 blockade represents a rational therapeutic strategy. These concepts may be tested in future trials as -secretase inhibitors that inhibit Notch sig- naling are currently in clinical development (60).
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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HEDGEHOG PATHWAY
| null | null |
The Hedgehog pathway is critical for many developmen- tal processes. In the absence of Hedgehog, a cell-surface transmembrane protein Patched (PTCH) acts to prevent high expression and activity of a seven membrane spanning receptor Smoothened (SMO). When extracellular Hedgehog is present, it binds to, and inhibits, PTCH, allowing SMO to accumulate and inhibit the proteolytic cleavage of the Ci protein with subsequent activation of nuclear transcription factors including Gli1 and Gli2. In the mammary gland, the
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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HEDGEHOG PATHWAY
| null | null |
Hedgehog pathway is required for normal development. Alterations in Hedgehog signaling result in defects in both embryonic and postnatal mammary gland development. Utilizing in vitro culture systems and NOD/SCID mice, Liu et al. (61) demonstrated that hedgehog signaling mediated by the polycomb gene BMI1 regulates the self-renewal of both normal and malignant human mammary stem cells. This process is blocked by specific inhibitors such as cyclopa- mine (11-deoxojervine). This compound has been shown to inhibit tumor growth in several mouse models. In order to reduce cyclopamine toxicity several cyclopamine deriva- tives such as IPI-96 have been developed, which are cur- rently in Phase I clinical trials.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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OTHER PATHWAYS
| null | null |
Other pathways that regulate the self-renewal and fate of cancer stem cells are being elucidated. In addition to path- ways such as Wnt, Notch, and Hedgehog, known to regu- late self-renewal of normal stem cells, tumor suppressor genes such as PTEN (phosphatase and tensin homolog on chromosome 10) and p53 have also been implicated in the regulation of normal and malignant breast stem cell self- renewal. It is believed that these pathways are deregulated in cancer stem cells, leading to uncontrolled self-renewal of these cells, which may generate tumors that are resistant to conventional therapies. Reduced PTEN expression is found in approximately 40% of HER2 amplified breast cancers, an alteration associated with trastuzumab resistance (62). PTEN downregulation increases the breast CSC population via Akt activation of the Wnt signaling pathway (63). The Akt inhibitor perifosine was able to partially block this pathway, reducing the CSC population. In a recent study Korkaya et al demonstrate that PTEN deletion in HER2-overexpressing breast cancer cells activates an IL6 mediated inflammatory feedback loop (64). This results in an expanded CSC popula- tion displaying an EMT phenotype, a process mediated by both autocrine and paracrine mechanisms, which in turn confer trastuzumab resistance. In addition, the authors demonstrate that interfering with this feedback loop utiliz- ing an IL6 receptor (IL6R) antibody reduces the CSC popula- tion and inhibits tumor growth and metastasis.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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OTHER PATHWAYS
| null | null |
Studies by Singh and colleagues (65) further our understanding of these pathways by showing interactions between the IL-8/CXCR1/2 axis and HER2 signaling in the
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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OTHER PATHWAYS
| null | null |
regulation of BCSCs. These studies confirm previous work showing independent roles for these pathways in regulating the self-renewal of BCSCs. CXCR1 is a receptor for the cyto- kine interleukin-8 (IL-8), and it has been shown that recom- binant IL-8 increased BCSC self-renewal as determined by the ability of these cells to form tumor spheres as well as by increased ALDH expression (66). Singh and colleagues show the clinical importance of IL-8 by directly measuring IL-8 levels in plural effusions and ascites from 10 patients with metastatic breast cancer. Of interest, they show a clear association between metastatic fluid IL-8 levels and ability of cells isolated from these effusions to generate primary and secondary tumor spheres. Reparixin, a small-molecule inhibitor of CXCR1/2, inhibits BCSC in mouse xenografts
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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OTHER PATHWAYS
| null | null |
(66). On the basis of this, a phase I clinical trial combin- ing reparixin with chemotherapy in women with advanced breast cancers has been initiated. Moreover, the studies of Singh and colleagues suggest that HER2 blocking agents may synergize with CXCR1/2 inhibitors in targeting the BCSC population. The simultaneous targeting of interacting extrinsic and intrinsic CSC regulatory pathways may result in more efficient elimination of BCSC populations improving patient outcome.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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OTHER PATHWAYS
| null | null |
In summary, the cancer stem cell model suggests that it may be necessary to target and eliminate cancer stem cells in order to eradicate cancers. Drugs that interfere with stem cell self-renewal or survival may prove effective in targeting these cell populations. Because normal and tumoral stem cells share many common regulatory pathways, it will be crit- ical to identify agents that have a therapeutic index between normal and cancer stem cells. A number of agents targeting breast cancer stem cell self-renewal pathways are now enter- ing early phase clinical trials (Table 2-1). These trials will pro- vide a direct test of the cancer stem cell hypothesis.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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OTHER PATHWAYS
| null | null |
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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OTHER PATHWAYS
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Smalley M, Ashworth A. Stem cells and breast cancer: A field in transit. Nat Rev Cancer 2003;3(11):832–844.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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OTHER PATHWAYS
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Dontu G, El-Ashry D, Wicha MS. Breast cancer, stem/progenitor cells and the estrogen receptor. Trends Endocrinol Metab 2004;15(5):193–197.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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OTHER PATHWAYS
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Reya T, Morrison SJ, Cark MF, et al. Stem cells, cancer, and cancer stem cells. Nature 2001;414(6859):105–111.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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OTHER PATHWAYS
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DeOme KB, Faulkin LJ, Bern HA, et al. Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. Cancer Res 1959;19(5):515–520.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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OTHER PATHWAYS
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Young LJ, Medina D, DeOme KB, et al. The influence of host and tissue age on life span and growth rate of serially transplanted mouse mammary gland. Exp Gerontol 1971;6(1):49–56.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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OTHER PATHWAYS
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Smith GH, Medina D. A morphologically distinct candidate for an epithe- lial stem cell in mouse mammary gland. J Cell Sci 1988;90(Pt 1):173–183.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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OTHER PATHWAYS
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Shackleton M, Vaillant F, Simpson KJ, et al. Generation of a functional mammary gland from a single stem cell. Nature 2006;439(7072):84–88.
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