A role of estrogen/ERα signaling in BRCA1-associated tissue-specific tumor formation

Abstract

Estrogen and its receptor alpha (ERa) have been implicated in the tissue-specific tumorigenesis associated with BRCA1 mutations. However, the majority of breast cancers developed in human BRCA1 mutation carriers are ERa-negative, challenging the link between BRCA1 and estrogen/ERa in breast cancer formation. Using a mouse model lacking the full-length form of BRCA1, here we show that ERa is highly expressed in the premalignant mammary gland and initiation stages of tumorigenesis, although its expression is gradually diminished during mammary tumor progression. We demonstrate that the absence of full-length BRCA1 increases sensitivity of cells to estrogen-induced extracellular signal-regulated kinase 1/2 phosphorylation and cyclin D1 expression. The absence of BRCA1 turns the proliferation of ERa-positive cells from a paracrine fashion to an autocrine or endocrine fashion. Consequently, BRCA1-mutant cells are sensitized to estrogen-induced cell proliferation in vitro and mammary tumorigenesis in vivo. These findings illustrate a molecular mechanism for estrogen/ERa signals in BRCA1-associated tissue-specific tumor formation, and identify several key elements in the estrogen/ERasignaling cascade that can serve as potential therapeutic targets for BRCA1-associated tumorigenesis.

BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival

“…6 D). Similarly, we did not observe any difference in cell cycle profile between E2-starved MCF7 cells before and after E2 suggest that estrogen (E2)-mediated survival of BRCA1-deficient cells is at the basis of BRCA1 tissue-specific tumor suppression (Elledge and Amon, 2002;Li et al, 2007).…”

Genetic instability and mammary tumor formation in mice carrying mammary-specific disruption of Chk1 and p53

“…The mutant glands appeared less dense than controls, and this abnormality was more impressive when the alveoli were visualized in high power images. Our previous studies indicated that mammary defects caused by Brca1 mutation could be rescued by p53 deficiency (Xu et al, 2001;Li et al, 2007). As Chk1 activity is regulated at least in part by Brca1 (Yarden and Brody, 2001), we were interested in investigating whether the developmental defect associated with Chk1 mutation could be rescued by simultaneous deletion of p53.…”

“…Thus, Chk1 deficiency yields profound abnormalities, as evidenced by mitotic catastrophe, which is much more severe than that caused by Brca1 mutation (Shen et al, 1998;Xu et al, 1999;Wang et al, 2004). This may account for the reason why absence of p53 could not rescue the lethality caused by Chk1 deficiency, although the absence of p53 is sufficient to suppress the lethality and growth defects associated with Brca1 mutation (Xu et al, 2001;Li et al, 2007). However, the abnormalities in multiple cell cycle checkpoints and cytokinesis in Chk1 mutant cells could eventually result in accumulation of genetic alterations that may cooperate with p53 deficiency to induce tumor formation.…”

BRCA1 affects global DNA methylation through regulation of DNMT1

“…;p53 +/− ) exhibit abnormalities in multiple organs/tissues, and eventually die of premature aging and tumorigenesis [16,17,[23][24][25][26][27]. The pleiotropic effect of BRCA1 deficiency correlates well with the fact that BRCA1 interacts with many proteins with important functions, and that BRCA1 acts as a transcription factor, which regulates expression of many genes involved in many biological processes [28,29].…”