Shaun D. McCullough, Yanfen Hu, and Rong Li

Department of Biochemistry and Molecular Genetics, Health Science Center, University of Virginia, Charlottesville, VA 22908, USA

Abstract: Women who inherit cancer-predisposing mutations in the BRCA1 gene have about 80% lifetime chance of developing breast cancer. BRCA1 mutation-associated tumors are often diagnosed as high-grade, typically display a basal epithelial phenotype, and proliferate rapidly. While somatic mutations of BRCA1 are rarely found in sporadic breast cancer cases, 3040% of the sporadic cases show reduced BRCA1 expression, supporting the notion that impaired BRCA1 function may contribute to the development of both familial and sporadic forms of breast cancer. Furthermore, low levels of BRCA1 expression have been linked with the occurrence of distant metastases in sporadic disease. Since cloning of the gene more than a decade ago, BRCA1 has been implicated in a large array of cellular functions, most notably DNA damage repair. However, the relationship between the known molecular functions of BRCA1 and the clinico-pathological features of BRCA1-associated tumors remains elusive. Why do BRCA1 mutations predominantly affect female breast and ovaries? Why do BRCA1-associated cancers tend to have a poor prognosis? How can the knowledge of BRCA1 function be translated into more targeted and efficacious therapies? In this review, we will discuss these important issues in light of some recent findings from laboratory and preclinical studies, which point to a need to look "outside the box" of epithelial cells by elucidating BRCA1 functions in the context of the unique tumor microenvironment.

Keywords: BRCA1, DNA repair, transcription, estrogen, tissue-specificity, estrogen receptor, tumor microenvironment.

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