Proliferation and ovarian hormone signaling are impaired in normal breast tissues from women with BRCA1 mutations: benefit of a progesterone receptor modulator treatment as a breast cancer preventive strategy in women with inherited BRCA1 mutations

Abstract

Women with inherited BRCA1 mutations have an elevated risk (40-80%) for developing breast and ovarian cancers. Reproductive history has been reported to alter this risk, suggesting a relationship between ovarian hormone signaling and BRCA1-related tumor development. BRCA1 interactions with estrogen receptor (ER) and progesterone receptor (PR) signaling were previously described in human breast cancer cell lines and mouse models. However, few studies have examined the effect of ovarian hormone regulation in normal human breast tissues bearing a heterozygous BRCA1 mutation. This study compares the proliferation level (Ki67) and the expression of ER, PR, and of the PR target gene, fatty acid synthase (FASN), in histologically normal breast tissues from women with BRCA1 mutations (BRCA1+/mut, n=23) or without BRCA1 mutations (BRCA1+/+, n=28). BRCA1+/mut tissues showed an increased proliferation and impaired hormone receptor expression with a marked loss of the PR isoform, PR-B. Responses to estradiol and progesterone treatments in BRCA1+/mut and BRCA1+/+ breast tissues were studied in a mouse xenograft model, and showed that PR and FASN expression were deregulated in BRCA1+/mut breast tissues. Progesterone added to estradiol treatment increased the proliferation in a subset of BRCA1+/mut breast tissues. The PR inhibitor, ulipristal acetate (UPA), was able to reverse this aberrant progesterone-induced proliferation. This study suggests that a subset of women with BRCA1 mutations could be candidates for a UPA treatment as a preventive breast cancer strategy.

Progesterone Receptor Isoforms, Nuclear Corepressor-1 and Steroid Receptor Coactivator-1 and B-Cell Lymphoma 2 and Akt and Akt Phosphorylation Status in Uterine Myomas after Ulipristal Acetate Treatment: A Systematic Immunohistochemical Evaluation

“…However, in a murine model of myoma xenografts, PR expression was found to be unchanged after mifepristone treatment [31], probably thanks to the conferred protection against proteasomal degradation [37]. UPA treatment even increased PR expression in 2 models of breast cancer xenografts [38, 39], as well as in the Fallopian tubes [40] and normal endometrium [41-43]. Our results suggest that UPA does not downregulate PR expression in uterine myomas but instead may prevent the turnover required for their appropriate activity, thereby explaining the antagonist action of UPA.…”

The use of selective progestin receptor modulators (SPRMs) and more specifically ulipristal acetate in the practice of gynaecology

“…Endometrial changes will be monitored throughout the study. In mouse xenograft models, bearing a BRCA1 mutation, UPA was capable of reversing aberrant progesterone‐induced proliferation, suggesting a potential role for UPA as a preventive breast cancer strategy . Other groups also reported anti‐tumorogenic effects of telapristone acetate (TPA) and UPA in mouse and rat models, or of UPA and APR19, a new selective and passive progestin receptor antagonist, supporting the potential role of these drugs in breast cancer therapy …”

“…UPA is currently used in only two instances: as emergency contraception and as a medical treatment of fibroids . Past and current research has also been conducted for other indications, such as daily contraceptive use, treatment of adenomyosis, endometriosis, and even for breast cancer treatment . In this article we will focus on the existing indications for UPA including mechanisms of actions, clinical data, side effects and safety, and also how the development of UPA might change the management of women's health.…”

Responsiveness of Brca1 and Trp53 Deficiency–Induced Mammary Preneoplasia to Selective Estrogen Modulators versus an Aromatase Inhibitor in Mus musculus

“…Research into breast cancer prevention in the setting of Breast Cancer 1 ( BRCA1 ) mutation continues due to considerations of efficacy and side-effects of current approaches (1–3) in conjunction with the possibility of developing more effective chemopreventive methods in the future (4–7). Tamoxifen (1,2,8,9), raloxifene (8,10) and letrozole (11) have all been proposed as risk-reducing antihormonals for women carrying germline BRCA1 mutations.…”

“…Tamoxifen is reported to reduce levels of mammary epithelial cell proliferation (25). Loss of BRCA1 can enhance estrogen and progesterone signaling in human breast cells (4,26,27) and GEMM with disrupted Brca1 alleles also demonstrate abnormal growth responses to estrogen and/or progesterone pathway stimulation (14,23,28). Loss of BRCA1 in cancer cells can interrupt the inhibitory action of tamoxifen on estrogen signaling (13,29).…”