CONCLUSION Since the identification of the BRCA1 tumor suppressor gene

Since the identification of the BRCA1 tumor suppressor gene more
than a decade ago, intense research in the field has implicated BRCA1 in
a disparate array of cellular processes. Despite the explosive knowledge
of BRCA1 in the literature, there exists a disconnect between the universal
nature of BRCA1 functions and the highly tissue-specific impact
of the BRCA1 mutations on tumorigenesis. Although BRCA1 mutation
carriers have a high risk of developing breast cancer, the genetic and
nongenetic modifiers that influence the penetrance of BRCA1 mutations
remain largely unexplored. Furthermore, the atypical clinicopathological
may be independent of LOH at the BRCA1 locus in the epithelium.
The potential tumor-promoting effect of BRCA1 loss in the stromal
Weber et al. found that, on a total-genome scale, LOH in BRCA1 mutation
expression of these angiogenesis-related genes (56, 105). Therefore,
40 McCullough, Hu, and Li
features of BRCA1-associated cancer suggests an involvement of BRCA1
in suppressing specific metastatic routes for cancer progression, although
a direct role of BRCA1 mutations in metastasis remains to be discerned.
A comprehensive understanding of these outstanding issues on BRCA1-
related cancer biology will go a long way to help develop more targeted
and effective prevention and treatment of the disease. A careful examination
of the current literature has led us to the proposal of an integrative
study of BRCA1 in the context of the unique mammary gland/tumor
microenvironment. Historically, studies of BRCA1 have been conducted
in breast epithelial/carcinoma cell lines. By looking “outside the box” of
epithelial cells and interrogating the impact of BRCA1 in both mammary
epithelial and stromal cells, we may be able to understand the etiology of
BRCA1 mutation-associated tumors in a systemic way. Given the loss of
BRCA1 expression in many sporadic breast cancer cases, continued
work in this direction also promises to have a broad application to breast
cancer therapies.
ACKNOWLEDGMENTS
NIH grants (CA118578 and CA93506). Due to limited space, we apologize
to those authors whose excellent work was not cited in this review.
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