The Molecular Basis Of The Tissue Specificity Of Brca1associated Tumors

3.1 Possible tissue-specific genetic instability

The exact molecular basis for the tissue-specificity of BRCA1 -related tumors remains elusive. Furthermore, it is unclear why somatic mutations of BRCA1 are rare in sporadic cancer cases. The highly tissue-specific character of BRCA1 -associated tumors stands in stark contrast with the ubiquitous nature of BRCA1 expression, as well as the generality and multiplicity of its reported functions. As reviewed above, compelling evidence strongly implicates BRCA1 in maintenance of genome stability. However, it remains unclear as to why deficiency of BRCA1 function in DNA damage response, a cellular event thought to be universally important in all cell types and both genders, would specifically increase the risk of breast and ovarian cancers in women. Several models have been proposed to explain the tissue-specific nature of BRCA1 -associated tumors. For example, it has been suggested that BRCA1 -deficient breast and ovarian epithelial cells may be more refractory to apoptosis than those in other tissues, thus allowing the former to accumulate additional genetic instability (65). Alternatively, the tissue-specific nature of BRCA1-associated tumors may arise from a higher frequency of LOH in the breast and ovarian epithelial cells (66). While maintenance of genetic stability is obviously an important part of the tumor suppressor function of BRCA1, it remains to be seen whether loss of this activity alone could fully account for the tissue- and gender-specific nature of BRCA1-associated tumors.

3.2 Modulation of ERa activity by BRCA1instability

The action of estrogen is critical to both normal mammary gland development and breast cancer (67-69). Aberrant changes of the expression and/or activity of ERa and its coregulators have been associated with breast carcinogenesis (70, 71). In light of the fact that cancer-predisposing mutations of BRCA1 predominantly affect the breast and ovary, two major estrogen-responsive tissues, the conundrum of "tissue-specificity" could be explained by a potential link between BRCA1 and estrogen action. In support of this notion, the wild-type BRCA1 protein has been implicated in the regulation of ERa-mediated gene expression. Initial studies by Rosen et al. demonstrated that the exogenous expression of BRCA1 resulted in downregulation of estrogen-stimulated expression of an estrogen-responsive reporter construct in human breast, prostate, and cervical carcinoma cell lines (72). Additional studies by this and other groups have shown that BRCA1 is physically associated with ERa-regulated promoters such as pS2 and regulates expression of the corresponding endogenous gene expression in breast cancer cell lines (40, 55, 73). Additional in vitro characterization has indicated that BRCA1 and ERa physically interact with each other through the amino-terminal region of BRCA1 and the ligand-binding domain (LBD) of ER-a in an estrogen-independent manner (40). Therefore, loss of the transcriptional corepressor function of BRCA1 in BRCA1-deficient cells may promote estrogen-dependent cell growth and neoplasia in the breast tissue. However, the tissue culture-based findings would have to be reconciled with the clinical observation that most BRCA1 -associated breast tumors are basal-like and ERa-negative (see below).

3.3 BRCA1 and regulation of estrogen biosynthesis

In addition to dysregulated transcriptional activity of ERa, prolonged estrogen exposure is also a well-documented risk factor for breast cancer (68, 74-78). Ovaries, specifically ovarian granulosa cells, are the primary source of estrogen in premenopausal women. This explains why early menarche and late menopause are associated with increased risks of breast cancer (79). Aromatase (Cyp19) is expressed in a restricted number of steroidogenic tissues including ovaries. The enzyme catalyzes the conversion from androgen to estrogen, the rate-limiting step in estrogen biosynthesis (80). Recently published work from our laboratories suggests that expression of BRCA1 in ovarian granulosa cells is inversely correlated with that of aromatase during steroidogenesis (81). Importantly, small interfering RNA (siRNA)-mediated knockdown of BRCA1 or its partner BARD1 resulted in elevated aromatase expression and its enzymatic activity in ovarian granulosa cells (81). In an independent study, Dubeau et al. made an intriguing observation that ovarian granulosa cell-specific Brca1 knockout mice develop ovarian and uterine tumors that still contain the wild-type Brcal gene (82). These in vitro and in vivo findings point to a cell nonautonomous role of BRCA1 in modulating the endocrine and/or paracrine actions of estrogen.

Endothelial Cells

Adipose Stromal Cells

Adipose Stromal Cells

Figure 2. Proposed impact of BRCA1 on different cell types within the mammary tumor microenvironment. E2 and T stand for 17beta estradiol and testosterone, respectively.

At menopause, ovarian estrogen production ceases and extragonadal sites such as adipose tissue become the prominent sources of estrogen (80, 83). In addition to the alteration in the source of estrogen, the capacity of estrogen as a signaling molecule changes from an endocrine to a localized paracrine/autocrine role (84). Indeed, elevated intratumoral aromatase expression and estrogen production are linked to the development of postmenopausal breast cancer (85, 86). This involves an intricate paracrine loop between tumor and the surrounding adipose stromal cells (ASCs): tumor cell-derived factors such as interleukin 6 (IL-6) and prostaglandin E2 (PGE2) stimulate aromatase expression and hence estrogen production in ASCs, which in turn promote estrogen-dependent growth of tumor cells (87-89). Such a "vicious cycle" is thought to facilitate breast cancer progression in the unique mammary tissue microenvironment. This also serves as the rationale for using aromatase inhibitors, such as letrozole, as efficacious agents for the treatment of postmeno-pausal breast cancer (90). In addition to the modulation of aromatase expression in ovarian granulosa cells (81), BRCA1 also appears to repress aromatase gene expression in ASCs (91, 92). Therefore, by blunting estrogen production in ovaries and mammary microenvironment, BRCA1 may reduce estrogen-mediated gene expression and suppress the initiation of estrogen-dependent tumorigenesis (Fig. 2). This function of BRCA1 in stromal cells may occur in parallel with the BRCA1-mediated repression of ERa transcriptional activity in mammary epithelial cells. Given the known carcinogenic effect of estrogen and its metabolites (93), elevated local estrogen levels due to BRCA1 deficiency in stromal cells may also contribute to genetic instability, thus compounding the consequence of impaired DNA repair capability in BRCA1 -defective epithelial cells within the same microenvironment.

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