Inhibition of Estrogen Signaling Reduces the Incidence of BRCA1-associated Mammary Tumor Formation

Abstract

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 BRCA1 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 BRCA1, and assessed the contribution of estrogen signaling to the incidence and progression of Brca1-mutated mammary tumors. Our in vitro 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 Brca1-mutant (Brca1co/coMMTV-Cre) 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, in vivo experiments showed that fulvestrant treatment did not alter the progression of ER-positive Brca1-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 BRCA1-mutated breast cancer.

Estrogen Receptor Status Oppositely Modifies Breast Cancer Prognosis in BRCA1/BRCA2 Mutation Carriers Versus Non-Carriers

“…A high number of loss-of-heterozygosity events at the BRCA1 genomic locus in ER-positive tumors from BRCA1 mutation carriers found in this study (83%) and in a study by Tung and colleagues (81%) indicates that BRCA1 impairment directly contributes to the formation of ER-positive tumors [28]. The mechanism explaining how ER signaling can contribute to worsened BC progression in BRCA1/BRCA2 mutation carriers is unknown; however, preclinical data demonstrated estrogen-dependent progression of mammary tumorigenesis in BRCA1-defficient cells [29,30]. Shah and colleagues have analyzed OncotypeDX in BRCA1/BRCA2 mutation carriers with ER-positive tumors and found a high proportion of patients with a high recurrence score who may benefit from adjuvant chemotherapy [31].…”

Inhibition of AKT suppresses the initiation and progression of BRCA1-associated mammary tumors

“…According to measurements of mammary gland density obtained using Branch software (ver. 1.1, 29 ), mammary glands of AKT1-deficient mice exhibited a significantly diminished ductal network (Fig. 2 B, and Supplementary Table 1 ).…”

Clinical behavior and outcomes of breast cancer in young women with germline BRCA pathogenic variants

“…There are several potential explanations for this lack of prognostic advantage in young BRCA -mutated patients with hormone receptor-positive breast cancer. Estrogen signaling was shown to promote tumor initiation and progression in BRCA -deficient cells 26 , 27 . Biological differences were reported between hormone receptor-positive breast cancers arising in patients with or without germline BRCA pathogenic variants 28 , 29 .…”