Effects Of BRCA1 On Progesterone-stimulated Proliferation And Migration Of Breast Cancer Cells And The Mechanism Study

Background and purposesBreast cancer is the most common malignancy of women. The incidence of breast cancer accounts for 7-10% of malignant tumors in women. In Western developed countries, breast cancer has ranked the first for the cause of women's death by cancer. The incidence of female breast cancer in China has also increased year after year, and age of onset is becoming younger. Breast cancer is caused by multifactors. A large number of studies have shown that breast cancer is involved in hereditary factors, one of which is BRCA1 gene. In the family of hereditary breast cancer, the mutation rate of BRCAl is up to 40-50%; in the family of hereditary breast and ovarian cancer, the mutation rate of BRCA1 is as high as 80%. And 80% of female carriers of BRCA1 mutations may eventually develop into breast cancer. BRCAl expression is also reduced in sporadic breast cancer,BRCA1 is a tumor suppressor gene, which plays an important role in transcriptional regulation, regulation of cell cycle, inhibition of cell proliferation, promotion of cell terminal differentiation, induction of apoptosis, repairing of DNA and maintaining genome integrity. BRCA1 is an important negative regulator of cell cycle.BRCA1 also plays an important role in the proliferation and migration of breast cancer cells. Fan reported that BRCA1 can inhibit estrogen receptor signaling. Burga found that the increased proliferation and migration ability of epithelial cell of BRCA1 mutants carriers may be related to epidermal growth factor receptor (EGFR) activation. Razandi and colleagues found that wild-type BRCA1 can inhibit extracellular estrogen-induced ERK activity by inhibiting the expression of ERK2. In addition, wild-type BRCA1 can also inhibit ERK activation and cell proliferation induced by the epidermal growth factor and insulin-like growth factor. On the onther hand, the study about the role of BRCA1 in breast cancer cell migration is relatively rare. In 1999, Seery reported that BRCA1 may be associated with sporadic breast cancer metastasis. In 2008, Yasmeen reported that BRCA1 was associated with breast cancer cell's migration and invasion, but without the in-depth study on the mechanism.Progesterone and its receptors also play an important role in breast cancer development. Clinical investigation showed that women, who takes the hormone replacement therapy, increased their breast cancer incidence. Even more, women with the combined use of progesterone and estradiol have higher incidence of breast cancer than those women with estrogen use alone. In the animal models of ovariectomized mice, the incidence of breast cancer in animals with combination use of estradiol and progesterone is lower than those with estrogen use alone. In contrast, the. effects of progesterone on proliferation and migration of breast cancer cells has been disputed. These differences in findings may be due to the different cell models.The current studies have shown that BRCA1 can regulate progesterone receptor activity. Our previous studies also have shown that BRCA1 can down-regulate the expression of progesterone receptors. However, whether BRCA1 regulates the breast cancer cell's proliferation and migration through down-regulating the expression of progesterone receptors has been rarely reported. This research hypothesizes that BRCA1 regulates the breast cancer cell proliferation and migration thgrough down-regulating progesterone receptors. Studying the relationships between BRCA1, progesterone receptors and the breast cancer cell proliferation and migration are important for in-depth understanding of the carcinogenic mechanism of BRCA1.MethodsMTT and the wounded healing experiments were used to analyse breast cancer cell proliferation and migration. Breast cancer cell line MCF-7 and T-47D were stimulated with progesterone and the effects of progesterone on breast cancer cell proliferation and migration were observed. BRCA1 was overexpressed in MCF-7 and T-47D cells to observe the BRCA1 effects on progesterone-stimulated breast cancer cell proliferation and migration.Results1. The effects of progesterone on cell proliferation and migration in cultured breast cancer cells.1) Progesterone stimulated the proliferation of breast cancer cell MCF-7 and T-47D;2) Progesterone promoted the migration of breast cancer cell line MCF-7 and T-47D;3) Progesterone down-regulated E-Cadherin expression.2. The mechanism study on BRCA1 regulated breast cancer cell proliferation and migration1) BRCA1 regulated the expression of progesterone receptor;2) Over-expression of BRCA1 decreased progesterone-stimulated breast cancer cell proliferation and migration. Conclusions1. Progesterone can promote breast cancer cell proliferation and migration;2. BRCA1 may inhibit the breast cancer cell proliferation and migration by down-regulation of progesterone receptors.The findings of this study suggest that functional loss or decreased expression of BRCA1 may promote proliferation and migration of breast cancer through up-regulating the expression of progesterone receptors in hereditary or sporadic breast cancer.