Tissue-Specific Tumor Suppression By Brca1

Germ-line mutations in the tumor suppressor gene BRCA1 increase the lifetime risk for breast cancer and ovarian cancer by up to ∼80% and ∼50%, respectively. Population-based studies also support a sex- and tissue-specific tumor suppressor function of BRCA1, but the mechanisms of this specificity are not fully understood. Somatic loss of the normal functioning allele in BRCA1 carriers is common in cancer development and additional somatic events, including mutations of PTEN and TP53, occur at high frequencies (detailed below). Research over the last two decades has described the role of the ubiquitously expressed BRCA1 in maintaining genomic stability through its function in DNA repair and cell cycle checkpoint control, in addition to its activity as a transcriptional regulator. In PNAS, Gorrini et al. shed light on the specificity of BRCA1’s tumor suppressor function in breast tissue. The authors identify an estrogen-induced pathway that promotes the survival of BRCA1-deficient mammary epithelial cells (MECs), as well as Brca1-deficient mammary tumor cells from oxidative stress-induced cell death (1). Oxidative stress plays important roles in cancer development and treatment (2). The NRF2-mediated antioxidant response pathway is the primary cellular defense against the cytotoxic effects of oxidative stress. Previously, Gorrini et al. showed how BRCA1 regulated the oxidative stress response through interaction with the NRF2 transcription factor to promote NRF2 stability and activation (3). Loss of BRCA1 resulted in defective NRF2 activation and reduced expression of NRF2-regulated antioxidant enzymes, leading to accumulation of reactive oxygen species (ROS) and cell death. Gorrini et al. now show that estrogen induces NRF2-regulated antioxidant genes in various cell types, likely through multiple pathways. They demonstrate that PI3 kinase activity is required, as treatment with a small molecular inhibitor of PI3K compromised expression of NRF2-regulated antioxidant genes. It is well established that PTEN mutations occur frequently in BRCA1-associated breast …