BRCA1 Inhibition of Estrogen Receptor Signaling in Transfected Cells
Abstract & commentary
Synopsis: The protein product of the gene BRCA1 inhibited estrogen-induced signaling by blocking the ability of estrogen receptor-alpha to initiate DNA transcription. This action of BRCA1 was specific to breast and prostatic cell lines and was not seen in a cultured cervical cancer cell line.
Source: Fan S, et al. Science 1999;284:1354-1356.
Mutations of the breast cancer susceptibility gene BRCA1 confer increased risk of breast, ovarian, and prostatic cancer, but it is not clear why the mutations are associated with these particular tumor types. In this study, Fan and colleagues performed transient transfection assays to assess the role of wild-type BRCA1 in immortalized cell cultures of breast, prostatic, and cervi- cal cancer. They found that the protein product of the gene BRCA1 inhibited signaling by the ligand-activated estrogen receptor-alpha (ER) to estrogen-response ele- ments of the DNA. BRCA1 did this by blocking the
function of the transcription activator called AF-2, which is a part of the estrogen receptor-alpha. This function of wild-type BRCA1 was seen in breast and prostate cancer cell lines, but not in cervical cancer cell lines. This means that if BRCA1 is mutated, the cellular impact of estrogen upon certain cell types, such as the breast, will be enhanced due to the absence of critical molecular machinery needed to constrain DNA transcription.
COMMENT By Sarah L. Berga, MD
In this same issue, I review the recent JAMA manuscript assessing the effect of HRT upon the risk of breast cancer. In their analysis, Gapstur et al of the JAMA article examined the differential effect of HRT upon specific breast cancer subtypes. While subtyping makes good theoretical sense, the validity of this approach depends upon the ability to appropriately subtype the tumors. I chose this companion manuscript from Science to demonstrate how recent gains in understanding the molecular basis of breast cancer might lead us to more meaningful parameters by which to subtype breast can- cers. Fan et al showed that wild-type BRCA1 dampens the molecular effect of estrogen upon breast cancer cells. It does this by preventing estrogen receptor-alpha from having its full effect when it binds to estrogen response elements (EREs) of the DNA. Fan et al demonstrate how
BRCA1 blocks the action of AF-2, which is one of two sites within ER-alpha that initiate transcription of the DNA. In other words, BRCA1 is a "transcription blocker." Knowing this, it is easy to see how mutations of BRCA1 might permit cellular growth in cell types that contain predominantly ER-alpha to become excessive when intracellular estrogen concentrations are high enough. BRCA1 apparently only regulates the actions of ER-alpha and not the actions of ER-beta.
As Fan et al point out, ER-alpha is the major estrogen receptor of mammary epithelia, but the effect of BRCA1 or its mutations are predicted to be nil in tissues that contain primarily ER-beta, such as neural or genital tissues. It stands to reason, then, that the oncogenic potential of estrogen to cause breast cancer would be seen only in, or would be greatest in, women with abnormal cellular machinery conferred by having a BRCA1 mutation. Thus, it would be critical to confirm if estrogen promotes breast cancer specifically in women with the BRCA1 mutation. Based on the foregoing JAMA manuscript, it would appear that, in general, postmenopausal hormone use does not increase the risk of breast cancer, but there may be certain subpopulations of women who would still be at risk. Obviously, it is important to be able to distinguish those at risk from those not at risk when counseling women about the long-term pros and cons of HRT.
Another interesting thought is that women with BRCA1 mutations might want to take both an estrogen and an ER-alpha-specific SERM, such as raloxifene,1 to gain the benefits of estrogen upon the brain while blocking the actions of estrogen upon the breast. Before we can evaluate the likely pros and cons of such a strategy, however, we need to better define which tissues contain predominantly ER-alpha and which contain predominantly ER-beta. The next few years ought to be very interesting! Hopefully, this gain in knowledge about the cellular mediators of estrogen action will permit us to be able to be much more specific about who needs what "hormonal cocktail."
Reference
1. Cummings SR, et al. JAMA 1999;281:2189-2197.
Which of the following best describes the cellular function of wild-type BRCA1?
a. Prevents estrogens from binding to the estrogen receptor-alpha, and thereby diminishes estrogen action
b. Mimics estrogen by binding to estrogen-response elements on the DNA and initiating transcription
c. Causes apoptosis in breast epithelial cells only
d. Nonspecifically promotes the cellular actions of estrogen in all cell types investigated to date
e. Inhibits estrogen-induced signaling by estrogen receptor-alpha by blocking transcriptional activation function
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