Why do BRCA1 mutations cause breast and ovarian cancers?

Today, May 8th, is #WorldOvarianCancerDay and I started thinking again about the above question. Why is it that mutations in BRCA1 and BRCA2 predispose to developing breast or ovarian cancer but usually not cancers in other tissues? Patients sometimes ask this during a genetic counselling session and it’s an astute question and a reasonable thing to ask but I haven’t yet found a great answer.

Commonly it’s a combination of “we don’t really know” and a more involved discussion that “some cell types are more dependent upon some genes than others, and BRCA1 and BRCA2 seem to be very important for preventing cancer development in breast and ovarian tissue”. Both of these are correct but I think that they are as unsatisfying to give as they probably are to receive. What is special about these genes and these tissues that links them together?

We know that BRCA1 and BRCA2 proteins have important roles in the DNA damage response. Your chromosomes are under daily assault from all types of mutagens and stresses and they suffer a variety of damage types. One of the worst types of damage is a double-stranded break, and BRCA1 and BRCA2 are important regulators of the double-stranded break repair pathways. Failure to fix these errors can lead to genome instability, one of the hallmarks of cancer (for more detail see Part 7 of Buddhini Samarasinghe wonderful series here). So, the role of BRCA genes as important tumor suppressors is well understood, but it still doesn’t explain why deficiencies in these proteins lead almost exclusively to breast and ovarian tumors.

The rather obvious thing to wonder is whether estrogen plays a role; this hormone is important for the growth and development of both breast and ovarian tissues, which are exposed to relatively high concentrations of estrogen. But BRCA1 breast tumors are commonly estrogen-receptor negative, meaning that the cancerous cells don’t express or depend on the protein that senses estrogen and communicates this signal into the cell. So it’s not a simple “tumor uses hormone signaling to promote it’s growth” situation, but perhaps it is some other aspect of high estrogen levels that promotes these cancers. Which brings us (finally) to the recent research linked to below. The authors have investigated the relationship between estrogen metabolism, DNA damage and the BRCA1 protein. Their results (and those of other groups working on the same problem) provide a possible answer answer to the link between estrogen and BRCA1:

• metabolites of estrogen can directly cause DNA damage by creating DNA adducts (molecules bound directly to the DNA nucleotides, interfering with DNA structure)
• DNA replication can’t proceed past these damaged nucleotides (i.e. the replication fork stalls) and BRCA1 is required to repair the damage
• and, BRCA1 directly suppresses the expression of an enzyme (CYP1A1) that helps to produce the damaging estrogen metabolites (although BRCA2 doesn’t appear to do this)

So: less BRCA1 protein leads to both 1) the increased production of damaging estrogen metabolites, and 2) the decreased ability to repair the DNA damage these molecules create. If these results can be replicated then they may finally provide an interesting and more satisfying answer to why BRCA1 and BRCA2 mutations lead to breast and ovarian tumors.