Angelina Jolie’s Double Mastectomy and NRF2: Any Connections?

There has been an increased awareness and many resulting questions following Angelina Jolie’s announcement that she has had a preventative double mastectomy to prevent the further spread of cancer.

The gene within her body that led to her decision is called BRCA1. BRCA1 is a tumor suppressor protein in carcinoma and normal cell types and protects normal cell’s DNA from uncontrolable cell growth. However when BRCA genes become mutated, they fail to protect the body from tumors and can lead to the spread of different types of cancers, including breast and ovarian cancer. Mutation of the BRCA gene in men can cause pancreatic, skin or prostate cancer. The study of this condition is extremely complex and requires more in depth understanding than what this article can provide. This article is for educational purposes only, consult with a medical professional to discuss personal conditions.

An analysis of Pubmed shows a number of different studies related to NRF2 and the BRCA-1 gene.

Readers of this web site know that oxidative stress (a major contributor to the etiology of cancer) occurs as the reactive oxygen species (ROS) and the cell’s antioxidant enzymes become imbalanced. The studies below investigate the effects of this in relation to BRCA and various cancers.

A recent study shows that a connection exists between NRF2 expression and the protection that the BRCA1 gene can provide. The study entitled, “Nrf2 is associated with the regulation of basal transcription activity of the BRCA1 gene.” The abstract states, “BRCA1 is closely related to the pathogenesis of breast cancer. The activity of BRCA1 promoter is regulated by transcriptional factors. The transcription factor Nrf2 (Nuclear factor-erythroid-2p45-related factor 2) is a potent transcriptional activator and plays a central role in inducible expression of many cytoprotective genes. In this report, we found that over-expression of Nrf2 stimulated BRCA1 expression, knockdown of Nrf2 attenuated BRCA1 expression. Nrf2 also interacted with CBP and p300 to form an active transcription complex, which could bind to the ARE (antioxidant response element) site on the BRCA1 promoter and activate its transcription by inducing histone acetylation. Our finding could lead to a better understanding of the development of breast cancer.” We look forward to further studies and results from the Department of Oncology, Department of Breast Surgery, Breast Cancer Institute, Shanghai Cancer Center, Shanghai Medical College and Fudan University who have conducted the research.

In this study: Low concentrations of diindolylmethane, a metabolite of indole-3-carbinol, protects against oxidative stress in a BRCA1-dependent manner, the researchers showed that the NRF2 activator indole-3-carbinol (I3C) metabolite 3,3-diindolylmethane (DIM) upregulated the expression of tumor suppressor protein BRCA1 in carcinoma and normal cell types. The up-regulation was dose and time sensitive, so it important to ready the entire study for details and not take a single statement out of context.

The finding of the study further showed that low concentrations DIM were able to protect cells from oxidative stress via the tumor suppressor BRCA1. The researchers found that the BRCA1 protein expression occurred in two breast cancer cell lines as well as prostate cancer, lung cancer and cervical cancer. Cells with low basal expression responded more positively than high basal expression suggesting the importance of NRF2 activation as a preventative measure rather than as a cure for disease.

The timing of the protection appears to make a big difference, i.e whether it occurs prior to the tumors developing. To quote from the study, “Our findings have implications for understanding chemoprevention and its limitations. Since DIM’s protective effects occurred at physiologic concentrations, it is reasonable to speculate that DIM blocks carcinogenesis, in part, by enabling normal cells to mount a more effective antioxidant response. This antioxidant response may include an increased ability of cells to repair oxidative DNA damage, since BRCA1 contributes to various DNA repair processes. Tumor cells often exhibit oxidative stress due to impaired antioxidant defenses. Thus, the presence of pre-existing cancer cells that are protected by antioxidants is a possible explanation for the mixed results obtained in clinical studies using antioxidants to prevent cancer. Here, the ability of DIM to promote survival of oxidatively stressed tumor cells could limit its activity as a chemoprevention agent”

The study above was followed up by a further paper published in 2009 entitled, “Low concentrations of diindolylmethane, a metabolite of indole-3-carbinol, protect against oxidative stress in a BRCA1-dependent manner.”  The abstract states, “The indole-3-carbinol (I3C) metabolite 3,3′-diindolylmethane (DIM) is a proposed cancer prevention agent for various tumor types, including breast cancer. Here, we show that DIM up-regulates expression of the tumor suppressor protein BRCA1 in carcinoma and normal cell types. Up-regulation of BRCA1 was dose and time dependent, and it was observed at physiologically relevant micromolar and submicromolar DIM concentrations when cells were exposed for 72 hours. Treatment with the parent compound (I3C) or DIM (1 micromol/L) protected against cell killing due to H(2)O(2) and other oxidants, and the protection was abrogated by knockdown of BRCA1. DIM stimulated signaling by the antioxidant transcription factor NFE2L2 (NRF2) through the antioxidant response element in a BRCA1-dependent manner. We further showed that DIM rapidly stimulated phosphorylation of BRCA1 on Ser (1387) and Ser (1524) and that these phosphorylations are required for protection against oxidative stress. DIM-induced phosphorylation of BRCA1 on Ser (1387) was dependent on ataxia-telangiectasia mutated. Finally, in our assay systems, H(2)O(2)-induced cell death was not due to apoptosis. However, a significant component of cell death was attributable to autophagy, and both DIM and BRCA1 inhibited H(2)O(2)-induced autophagy. Our findings suggest that low concentrations of DIM protect cells against oxidative stress via the tumor suppressor BRCA1 by several distinct mechanisms.”

The 2010 study “Redox regulation in cancer: a double-edged sword with therapeutic potential.” The message from this study validates the previous two. Namely that prevention is better than cure. The study states that, “Nrf2 plays an essential role in maintaining cellular homeostasis and hence represents a critical target for prevention of oxidative stress- or inflammation-associated carcinogenesis.”

Thanks to Angelina Jolie for being willing to share the news of her health condition publicly and raising awareness of breast cancer and spur interest in finding a cure for this disease.

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