it plays several important physiological and pathological roles in not only reproductive system but also other systems .
estrogen disorder results in various diseases , such as endometrial diseases , skeletal diseases , and reproductive system tumors .
increasing attention has been paid to revealing of the functions of estrogen in physiological and pathological conditions .
estrogen receptors ( er )  and  , the two well established nuclear estrogen receptors , have different physiological functions depending upon their various distributions .
lots of evidences show that estrogen induces the proliferation of cancer cells in breast , uterus , and ovarian cancer through er. on the contrary , activation of er can reverse this effect .
notably , a novel transmembrane estrogen receptor , known as g - couple estrogen receptor ( gper ) , was found .
er are involved in the initiation , migration , and progression of estrogen - related multiorgan cancers , such as breast cancer , ovarian cancer , prostate cancer , testicular cancer , liver cancer , and lung cancer as well .
although increasing studied are focused on the roles of gper-1 in different types of cancers , the functions of gper-1 in cancers remain unclear yet .
characteristics and functions of reproductive system cancer will be summarized and discussed in the present review .
g - protein - coupled estrogen receptor-1 ( gper-1 ) , a seven - transmembrane - domain receptor localized in cell surface , was first identified in 1996 .
gper-1 is detected broadly in numerous human tissues , such as breast , prostate , ovary , placenta , subcutaneous adipose , visceral adipose , arteries , vessels , heart , liver , lung and intestine tissues .
gper-1 is a member of gpcr superfamily , which is structurally unrelated to the classical er and er. there are four transcriptional variants encoding 375 amino acids composing seven transmembrane proteins .
but gper-1 binding domain exists inside the plasma membranes and the endoplasmic reticulum [ 58 ] .
estradiol , the major type of estrogen , binds to gper-1 with a high affinity to gper-1 while the other two isoforms , estrone and estriol , have very low binding affinities [ 5 , 9 ] .
furthermore , numbers of environmental estrogen bind to gper-1 and activate the downstream signaling pathways , such as bisphenol a , genistein , and nonylphenol .
gper-1-specific compound 1 ( g-1 ) is a specific agonist of gper-1 , which has no function of er and er and was identified using virtual and biomolecular screening in 2006 .
g-1 has been widely used as a target tool to evaluate the function of gper-1 in different cells and disease models .
gper-1 mediates both genomic and nongenomic response with its ligands . to date , gper-1 signaling pathways have not been fully elucidated yet .
the binding ligands of gper-1 , such as estrogen , g-1 , tamoxifen , and ici182,780 , cross the plasma membrane and bind to the gper-1 on endoplasmic reticulum where they activate its  and  subunits and subsequently activate both src and adenylyl cyclase ( ac ) leading to the intracellular camp production .
the phosphorylation of src induces matrix metalloproteinase ( mmp ) production , which cleaves pro - heparan - bound epidermal growth factor ( pro - hb - egf ) releasing free hb - egf .
hb - egf binds to the egfr leading to activation of multiple molecules such as ras , pi3k , akt , and erk1/2 .
the downstream signal of pi3k and akt results in several nuclear receptors activation which is closely related the proliferation and migration of cancer cell .
gper-1 also binds to the g - couple protein  subunit and activates the phospholipase c ( plc ) , ac , and camp .
activated plc results in inositol triphosphate ( ip3 ) production , which further binds to its receptor and leads to intracellular calcium mobilization .
breast cancer is generally classified into estrogen receptor positive ( er+ ) and er negative ( er ) . in clinical practices ,
the endocrine treatments such as tamoxifen and aromatase are recommended in the er positive breast cancers , while there is no benefit in the er negative cancers .
gper-1 is widely expressed in both of these breast cancer types and the primary breast cancers .
recent clinical study results showed that the expression of gper-1 might correlate with clinical and pathological poor outcome biomarkers .
other results also showed that the expression of gper-1 was inversely correlated with the er expression .
coexpression of gper-1 and er was found in almost 24% patients with inflammatory breast cancer , while 19% only express er and 46% only express gper-1 .
the gper-1 mrna levels were significant higher in er positive breast cancer cells compared to er negative cancer cells , and the expression of gper-1 depends on er mrna level .
interestingly , gper-1 preformed a different proliferation manner in er positive mcf-7 breast cancer cell line .
g-1 enhanced migration of mcf-7 breast cancer cells by activating erk1/2 and egfr signaling pathway , which is tremendously attenuated by g15 .
the other evidences also approved that gper-1 is an initiator of tamoxifen resistance in breast cancers [ 1921 ] .
the promotion roles of gper-1 in cancer cells proliferation and migration may be correlated with the autolysis of calpain 1 , cleavage of cyclin e , or the expression of target gene .
there are also some studies which found that gper-1 inhibits the growth of er positive mcf-7 cells , which is probably through g - couple  and  subunits activating without camp signal activation [ 2124 ] . however , combination treatment with g-1 and her2 antibody trastuzumab exerted an additive growth inhibitory effect on breast cancer cells .
thus , gper-1 inhibits er positive breast cancers proliferation which is a potential target for er positive breast cancers and drug - resistant breast cancer .
deficiency of er in breast cancer is correlated with poor response to endocrine therapy . in er negative breast cancers , gper-1 stimulates the erk1/2 through the egfr / mapk signal cascade , inducing target gene like c - fos expression , which is involved in the progressing of breast malignancies [ 2729 ] .
estrogen and antiestrogens can also promote the production of the early growth response-1 ( egr-1 ) , connective tissue growth factor ( ctgf ) , and insulin - like growth factor 1 ( igf-1 ) through the gper-1 [ 28 , 30 , 31 ] .
grp30 activation stimulated breast cancer cells migration through ctgh , cxc receptor ( cxcr1 ) , and notch pathways . furthermore , gper-1 agonist g-1 promoted inflammation in breast cancers .
gper-1 was reported to affect the deformation of breast glandular structure inducing the malignant transformation of breast tissue .
gper-1 can also induce expression of cancer - associated fibroblasts ( cafs ) in tumor microenvironment [ 34 , 35 ] . on the contrary
, a recent study showed that activation of gper-1 by g-1 resulted in g2/m - phase arrest and induction of mitochondrial - related apoptosis .
the other studies also proved that g-1 treatment suppressed the growth of skbr3 cancer cells and increased the survival rate by inducing the erk1/2 signal activation [ 36 , 37 ] .
1520% of breast cancers are included in triple negative breast cancers ( tnbc ) , characterized by lack of er , progesterone receptor ( pr ) , and egfr2 ( her-2 )
. a higher rate of recurrence and aggressive biological features were found in younger females [ 38 , 39 ] .
gper-1 expression was found in majority of tnbcs patients . in the gper knockdown mice model , the proliferation of tnbcs ,
these findings suggest that gper plays a key role in putative mechanism for tnbcs and gper might be a therapeutic target for tnbcs .
snps of gper-1 , histone acetylation , and transcription factor recruitment were significantly associated with tumor size and histological grading [ 42 , 43 ] .
gper rna as well as gper-1 protein presents in both primary and malignant ovarian tumor tissues . the expression of gper-1 was significantly increased in ovarian carcinomas compared to pericarcinomatous tissues impendent with the expression of egfr , er , and er .
estrogen and g-1 induce ovarian cancer cell growth responses via egfr - mapk signaling pathways .
furthermore , gper-1 promoted the migration and invasion of ovarian cancer cells ovcar5 which is characterized by negative er and positive gper by increasing the expression mmp-9 [ 48 , 49 ] .
atrazine , one of the most common pesticide contaminants , promoted ovarian cancer cells proliferation via induction of erk and expression of estrogen target gene through gper-1 pathway .
but other studies results showed that g-1 suppressed proliferation and induced apoptosis of human ovarian cancer cells probably through inhibition of cell cycle progression in g2/m - phase in ovarian carcinomas [ 51 , 52 ] . 

gper-1 has been shown to be involved in a variety of hormone - dependent cancers .
it is well understood that estrogens play a critical role in pathological germ cell proliferation in testicular germ cell tumors .
gper-1 seems to be involved in modulating the growth of estrogen dependent testicular cancer cells .
estrogen induces the high expression of gper-1 correlated with low levels of er in human testicular carcinoma in situ and seminomas [ 53 , 54 ] .
bisphenol a , a common environmental estrogen , can also promote the proliferation of testicular seminomas cells through gper-1 .
the above findings suggested that gper-1 may be a potential therapeutic target [ 56 , 57 ] .
estrogen has an efficacy for advanced prostate cancer ( pc ) via the mediation of the classical estrogen receptors .
the effects of er on pc growth and metastases have different mechanisms in different cellular microenvironments .
the expression of gper-1 is higher in the preneoplastic lesions and normal areas of benign prostate than the basal epithelial cells .
g-1 , the selectively activating gper-1 , inhibited the growth of multiple pc cells in vitro and in vivo through erk1/2 and c - jun / c - fos signaling pathways , which indicates that the g-1 may be a new option for pc through targeting gper-1 .
g-1 inhibited castration - resistant phase but had no effect on androgen - sensitive tumors .
the antitumor effect of g-1 on cr tumors was related to necrosis ( approximately 65% ) accompanied with neutrophils infiltration .
g-1 can also upregulate neutrophil - related chemokines and inflammation - mediated cytokines in the cr tumors . in one word
there are other studies which proved that gper-1 induced proliferation , differentiation , and drug resistance of lung cancers [ 63 , 64 ] , thyroid cancers , bladder cancers , and oral squamous carcinomas .
more studies to reveal the functions and mechanisms of gper-1 in the other system cancers are warranted .
majority of the study results addressed that activation of gper-1 by estrogen and g-1 results in the downstream signals and target genes activation , which promotes the proliferation , migration , and invasion of cancer cells . and
this effect is in nonclassical er expression dependent manner in most cancers except for ovarian cancers .
it is interesting that several other studies showed that g-1 , the special agonist of gper-1 , promoted the expression of gper-1 and inhibited the proliferation of er negative breast cancer cells , ovarian cancer cells , and prostate cancer cells .
the opposite effects of gper-1 in cancer cells may be associated with the epigenetic of gper-1 , such as the snps and histone acetylation .
the different cell types , tumor microenvironment , and hormonal level may also affect the functions of gper-1
. controversies still exist on the gper-1 localization and related signaling pathways , in particular the potential action as proapoptotic mediator . since the function and mechanisms of gper-1 are still unclear , more researches and clinical studies are strongly warranted to clarify the different function and mechanisms in different cancer types and conditions .
 the g - protein - coupled estrogen receptor-1 ( gper-1 ) , also known as gpr30 , is a novel estrogen receptor mediating estrogen receptor signaling in multiple cell types . 
 the progress of estrogen - related cancer is promoted by gper-1 activation through mitogen - activated protein kinases ( mapk ) , phosphoinositide 3-kinase ( pi3k ) , and phospholipase c ( plc ) signaling pathways . however , 
 this promoting effect of gper-1 is nonclassic estrogen receptor ( er ) dependent manner . 
 in addition , clinical evidences revealed that gper-1 is associated with estrogen resistance in estrogen - related cancer patients . 
 these give a hint that gper-1 may be a novel therapeutic target for the estrogen - related cancers . 
 however , preclinical studies also found that gper-1 activation of its special agonist g-1 inhibits cancer cell proliferation . 
 this review aims to summarize the characteristics and complex functions of gper-1 in cancers . 
1. Introduction
2. The Characteristics of GPER-1
3. Functions of GPER-1 in Reproductive System Tumors
4. GPER-1 in Other Tumors
5. Conclusion