4.1 Is BRCA1-associated tumorigenesis estrogen-dependent?
The relevance of estrogen/ERa to the etiology of BRCA1 -associated tumors has been a long-standing clinical conundrum. BRCA1 -associated tumors are largely ERa-negative (6) and their gene expression profile resembles that from basal epithelial cells in the mammary gland (94, 95). On the other hand, prophylactic oophorectomy, which removes the major source of circulating estrogen in premenopausal women, significantly reduces risk of breast cancer in BRCA1 -mutation carriers (96, 97). Consistent with the findings in human (96, 97), oophorectomy decreases the incidence of mammary tumor formation in the MMTV--BRCA1'' mouse model (98). In addition, tamoxifen has been shown to be effective in reducing the risk of contralateral tumors in BRCA1 -mutation carriers (99). Epidemiological evidence also suggests that hormonal exposure and obesity in adolescence, which are well-known risk factors for sporadic breast cancer, can significantly affect breast cancer onset for BRCA1 -mutation carriers (12).
How could one reconcile the ERa-negative feature of BRCA1-associated tumors with the apparent impact of estrogen exposure on the disease risk? One possible explanation for the aforementioned paradox is that ERa-positive BRCA1 -deficient cells may evolve to become ERa-negative tumors during the disease progression. Consistent with this notion, early-stage mammary tumors from MMTV-B^C^7~~ knockout mice are largely ERa-positive, whereas late-stage tumors usually lack ERa expression (100) (Chuxia Deng, NIH, personal communication). Therefore, it is possible that modulation of estrogen production and/or the transcript-tional activity of ERa by wild-type BRCA1 in stromal and epithelial cells, respectively, may play a critical role in suppressing the initiation of BRCA1 -associated tumors. In an alternative scenario, normal ERa-positive cells in the same microenvironment could influence the behavior of BRCA1-deficient, ERa-negative preneoplastic cells through a paracrine mechanism. Obviously, an in-depth investigation of the BRCA1-estrogen connection will be of great importance to more targeted prevention and treatment of BRCA1 -associated cancers. The same research may also shed light on the functional consequences of reduced BRCA1 expression associated with many sporadic breast cancers (6).
4.2 Why do BRCA1-associated cancers have a poor prognosis?
BRCA1-associated tumors are usually diagnosed as high-grade infiltrating ductal carcinoma (99). Patients with BRCA1 -associated breast tumors tend to have a poorer prognosis than those with sporadic tumors, suggesting that loss of BRCA1 function may lead to a more aggressive progression of breast cancer. Interestingly, a recent report suggests a high incidence of brain metastasis in BRCA1-associated cancer cases (101). Contrary to what has been observed in sporadic breast cancer, BRCA1 mutation-associated poor prognosis often occurs in node-negative cases, where tumors do not spread to axillary lymph nodes (6). It was postulated that BRCA1-associated tumors might choose metastatic routes other than the lymphatic system, perhaps through newly formed blood vessels surrounding the tumors (6). Just as proposed for the initiation of BRCA1 -associated breast tumors, the exact pattern and route for the progression and spreading of these tumors may also be determined by an intricate interaction between BRCA1 -deficient tumor cells and the surrounding stroma. Is there any evidence in support of such a hypothesis?
Using a recently popularized three-dimensional cell culture system that mimics the in vivo mammary microenvironment (102, 103), Furuta et al. showed that BRCA1 depletion by shRNA interference in the immortalized mammary epithelial cell line MCF10A disrupts normal acinar morphogenesis in vitro (104). Reduction of BRCA1 in the MCF10A cell line led to aberrant cell proliferation and failure to respond to extracellular matrix (ECM)-dependent differentiation signals. Of particular interest is the observation in this study that treatment of BRCA1-depleted MCF10A cells with conditioned medium from control counterparts partially restored the ability of these BRCA1-depleted cells to complete three-dimensional acinar morphogenesis in vitro. These results are consistent with the possibility that mammary epithelial cells secrete an autocrine/paracrine factor in a BRCA1-dependent fashion to promote normal differentiation. In support of this notion, a follow-up study from the same group found that BRCA1 directly represses transcription of angiopoietin (ANG1), the product of which acts in a paracrine manner to promote endothelial cell survival and vascularization (56). In an independent study, BRCA1 was shown to repress ERa-dependent transcription and secretion of vascular endothelial growth factor (VGEF) in breast cancer cells (105). Of clinical importance, both studies demonstrated that cancer-predisposing mutants of BRCA1 fail to reduce the expression of these angiogenesis-related genes (56, 105). Therefore, these studies raise a distinct possibility that loss of BRCA1 in mammary epithelial cells may have a significant impact on the behavior of the stromal cells in the tumor microenvironment, which in turn may influence the metastatic outcome of the BRCA1 -associated cancer (Fig. 2).
Cytogenetic analyses of clinical samples also shed some intriguing light on the genetic instability of BRCA1 -associated tumor and the surrounding stroma in the same microenvironment. In a recent report, Weber et al. found that, on a total-genome scale, LOH in BRCA1 mutation carriers was similar between the breast tumor cells and the associated stroma (106). Further, LOH at the BRCA1 locus of several patients was only observed in the breast tumor stroma (106). These observations suggest a role for stromal BRCA1 in suppressing tumor progression that may be independent of LOH at the BRCA1 locus in the epithelium. The potential tumor-promoting effect of BRCA1 loss in the stromal compartment may be similar to that of stromal p53 mutations recently demonstrated in breast and prostate tumors (107, 108). Lastly, it has been recently reported that malignant human breast cancer epithelial cells can fuse with and transform mouse stroma (109). Therefore, it will be of interest to see whether the increased genetic instability due to loss of BRCA1 in the microenvironment may result in fusion of the epithelial and stroma components.
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