Simple SummaryParathyroid-hormone-related protein (PTHrP) is produced in normal breast and breast cancer cells and causes bone destruction when expressed by cancer cells that have spread to the bone. When PTHrP is released, it binds to its receptor on neighboring bone cells; however, we now understand that PTHrP does not behave this way in breast cancer. Instead of binding to a receptor, PTHrP moves around inside the cells, which results in pro- or anti-tumor effects. This has caused confusion in the field since studies sometimes report conflicting results after deleting or increasing the expression of PTHrP. This review will improve our understanding of PTHrP and breast cancer by discussing the unique role PTHrP plays in breast cancer and how PTHrP signaling inside the cell and the different regions of PTHrP may play a role in the observed discrepancies.AbstractParathyroid-hormone-related protein (PTHrP) is a protein with a long history of association with bone metastatic cancers. The paracrine signaling of PTHrP through the parathyroid hormone receptor (PTHR1) facilitates tumor-induced bone destruction, and PTHrP is known as the primary driver of humoral hypercalcemia of malignancy. In addition to paracrine signaling, PTHrP is capable of intracrine signaling independent of PTHR1 binding, which is essential for cytokine-like functions in normal physiological conditions in a variety of tissue types. Pre-clinical and clinical studies evaluating the role of PTHrP in breast cancer have yielded contradictory conclusions, in some cases indicating the protein is tumor suppressive, and in other studies, pro-growth. This review discusses the possible molecular basis for the disharmonious prognostic indications of these studies and highlights the implications of the paracrine, intracrine, and nuclear functions of the protein. This review also examines the current understanding of the functional domains of PTHrP and re-evaluates their role in the unique context of the breast cancer environment. This review will expand on the current understanding of PTHrP by attempting to reconcile the functional domains of the protein with its intracrine signaling in cancer.