Inhibition of Estrogen Signaling Reduces the Incidence of -associated Mammary Tumor Formation.

BRCA1-deficient breast cancer is a very well-known hereditary cancer. However, except for resection of normal mammary glands and ovaries, there is no acceptable measure for proactively preventing tumor development. Importantly, inherited mutations are closely associated with tumors in hormone-responsive tissues. Here, we examined the effects of estrogen on the accumulation of genetic instabilities upon loss of , and assessed the contribution of estrogen signaling to the incidence and progression of -mutated mammary tumors. Our studies showed that treatment of BRCA1-depleted breast cancer cells with estrogen induced proliferation. Additionally, estrogen reduced the ability of these BRCA1-knockdown cells to sense radiation-induced DNA damage and also facilitated G1/S progression. Moreover, long-term treatment of -mutant () mice with the selective estrogen receptor (ER)-α degrader, fulvestrant, decreased the tumor formation rate from 64% to 36%, and also significantly reduced mammary gland density in non-tumor-bearing mice. However, experiments showed that fulvestrant treatment did not alter the progression of ER-positive -mutant tumors, which were frequently identified in the aged population and showed less aggressive tendencies. These findings enhance our understanding of how ER-α signaling contributes to BRCA1-deficient mammary tumors and provide evidence suggesting that targeted inhibition of ER-α signaling may be useful for the prevention of -mutated breast cancer.