Preliminary Study Of The Follicle-Stimulating Hormone And The Pathogenesis Of Postmenopausal Breast Cancer

BackgroundBreast cancer is one of the most common cancers in women and one of the main causes of cancer death worldwide. The hormone level is different in the postmenopausal women when compared to the premenopausal one, as the failure of the ovary. The pituitary secretes more gonadotropin hormones including follicle-stimulating hormone (FSH) and luteinizing hormone (LH) into blood without the feedback of estrogen. It is estimated that women will live in a high gonadotropin hormone level in a third of their all lifetime.Estradiol and its receptor play a critical role in breast cancer endocrinal treatment, however not all of the patients benefit from hormone therapy. It has been found that many other hormones participate in the pathogenesis of breast cancer, such as prolactin, human chorionic gonadotropin, LH. It has been found that serum FSH was related with the recurrence free survival and overall survival rate of breast cancer and high serum level of FSH cause short overall survival rate.It has also been found serum FSH of the breast cancer has a positive relationship with the Her-2expression. However, it is not clear that the FSH participate into the pathogenesis of postmenopausal breast cancer.It is recognized that the follicle stimulating hormone receptor (FSHR) was expressed only in the granulosa and sertoli cells. However, it appeared in many other tissues such as ovarian cancer, prostate cancer, and endometrial cancer in recent researchs. It involved in the proliferation, metastasis and apoptosis of these cancer cells. Remarkably, FSH played as the main reason of osteoporosis in the postmenopausal women published at "Cell" lead a deep understanding of FSH in postmenopausal diseases. Recently, it was found that FSHR is selectively expressed on the surface of the blood vessels of a wide range of tumors. It is not clear whether the breast cancer cell expressed the FSHR.It is still a mystery that FSH enrolled in the postmenopausal breast cancer pathogenesis concerning the high FSH level in postmenopausal women.ObjectiveTo study the difference of serum gonadotropin hormone level between breast cancer and control group in postmenopausal women; To investigate the internal relations of FSH and the tumor clinical classfication,lymph node metastasis, and the status of ER,PR,Her-2and Ki67; To study the expression of FSHR in breast cancer cell line and breast cancer tissues; To study whether FSH induce proliferation and metastasis of breast cancer cell line and the exact mechanism in vitro and in vivo.MethodPart1:Clinical datas of187postmenopausal women diagnosed of breast cancer and374postmenopausal compared group, who suffer from normal gynecological inflammatory such as cervicitis,were collected for statistic analysis.Part2:Two breast cancer cell line (Bcap-37and MDA-MB-231) have been used to study whether the FSH induce proliferation and metastasis in vitro.To detect the cell proliferation in vitro,we use the MTT method; Western Blot has been used to detected the cell pathway changing after the treatment of FSH. The scratch test and Matrix transwell were used to detect the migration and invasion of the two cell line treated with FSH.Part3:Study the promoting proliferation effect of FSH in vivo.We established a postmenopausal animal model of Balb/c nu/nu mouse by ovariectomized (OVX). The experiment was divided into four groups:Sham, OVX control, using GnRha after OVX, using GnRHa followed FSH after OVX.Part4:Study of the expression of FSHR in breast cancer cell lines and tissues. RT-PCR and Reverse-PCR has used to investigate the expression of FSHR in these breast cancer cell lines:Bcap-37, MDA-MB-231, Mcf-7, T-47D, SK-BR-3and BT-474. The expression of FSHR in17samples of breast cancer tissue was also been detected by RT-PCR.ResultsPart1:The serum level of FSH,LH in postmenopausal breast cancer were higher than control group (61.83±1.475vs.48.13±1.256IU/L;27.83±0.74vs.23.88±0.6499IU/L).FSH has a positive correlation with Ki67and Her-2expression in postmenopausal breast cancer, while LH only have positive correlation with Ki67expression. No significant association has been found between gonadotropins and breast cancer clinical classification, clinical grade, lymph node metastasis, ER and PR status.Part2:It has been found that FSH could promote the Bcap-37and MDA-MB-231cell proliferation in vitro. The FSH induce the proliferation and metastasis of the two cell line by activated EGFR/ERK1/2signal pathway.Part3:A high concentration of FSH (-100IU/L) could promote the proliferation of breast cancer cell line Bcap-37and MDA-MB-231in vivo. Part4:The FSHR was not expressed in all of the breast cancer cells tested and breast cancer tissue.ConclusionPostmenupausal breast cancer patient favored a high serum gonadotropin level compared with normal gynecological inflammatory patients.The serum FSH level has a positive correlation with the Her-2and Ki67expression in postmenopausal breast cancer,while LH has a positive corelation with Ki67expression. The FSH cound promote the proliferation and metastasis of breast cancer cell line Bcap-37and MDA-MB-231by activated the EGFR/ERK1/2pathway in vitro.A high concentration of FSH (-100IU/L) may also promote the proliferation of breast cancer cell line in vivo. However, we haven’t found the expression of FSHR in breast cancer cell line been tested and breast cancer tissue. Further studies are needed to charlify the exact mechanism between FSH and postmenopausal breast cancer.