The Genetics of Breast Cancer Risk

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October is National Breast Cancer Awareness Month and everyone, from patient advocacy groups to retail stores to even the NFL, is thinking pink. Science in Society caught up with Dr. Virginia Kaklamani, oncologist and director of translational breast cancer research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, who will speak at the center’s Lynn Sage Breast Cancer Town Hall Meeting on Sunday October 24th. We asked about what factors in to breast cancer risk, and where this research is headed next.

What do we already know about genes and breast cancer risk?
We know that around 20-30% of breast cancers are due to certain genetic changes, called mutations. We have identified a few genes that, if they don’t work well, predispose [people] to getting breast cancer. The most common ones are BRCA1 and BRCA2. Then there are other genes such as PTEN and P53 – these are much more rare mutations. But still, even BRCA1 and 2 are present in only around one in 500 individuals. So again, the minority of breast cancers are due to changes in those genes.

We think that the rest of the breast cancers are what we call sporadic, meaning that they are due to other factors that do not seem to be related to genes, such as a patient’s age – the older we are, the higher our risk of breast cancer. It could be the use of alcohol – we know that moderate alcohol consumption increases breast cancer risk. Women who have a longer reproductive cycle (women who start menstruating at a younger age and go into menopause at an older age) tend to have a higher risk, as do women that have children at an older age or do not have children at all.
Dr. Virginia Kaklamani (photo courtesy of the Robert H. Lurie Comprehensive Cancer Center)Dr. Virginia Kaklamani (photo courtesy of the Robert H. Lurie Comprehensive Cancer Center)
What other genes are you investigating for a relationship to breast cancer?

There are actually a lot of other gene mutations that increase the risk of breast cancer. [They don’t increase the risk] by as much as BRCA1 and 2 do, but they are way more common in the population, so their impact in breast cancer risk is actually higher. For example, BRCA1 and 2 mutations can increase the risk of breast cancer by eight to ten fold. These other gene mutations increase the risk by one and a half percent. So we’re talking about much lower risks. But, if BRCA1 and BRCA2 are present in one in 500 individuals, these genes are present in five or ten percent of the population. So their impact is much more broad.

One of these genes is called TGF-beta. We’ve found that a change in the receptor of TGF-beta can increase the risk for breast cancer. A receptor is a protein, usually on the surface of the cells, that activates a pathway in the cells. TGF-beta is actually an interesting molecule because, in non-cancer cells, it inhibits growth, but in cancer cells it seems to accelerate the growth. And we still don’t where that switch happens, from a protective to a detrimental factor in cancer.

Another gene is called adiponectin, which actually has to do with diabetes, obesity, and breast cancer. We know that there is connection between obesity, diabetes and breast cancer, and again it seems that changes in adiponectin can increase the risk for breast cancer.

Also, we think that when these genes are involved in increasing the risk of breast cancer, it’s not just one gene, like we see with BRCA1 or 2, but it’s a lot of genes, and the combination effect of all of the genes increases the risk.

Are women being tested for the TGF-beta and adiponectin genes?
We do not have clinical testing for these genes yet; we’re trying to figure out how significant they are. We’re taking individuals with cancer, individuals without cancer, and looking at those two large groups of people and trying to figure out what the differences are and which genes one group has that the other doesn’t have. Once we finish that stage and identify the genes that we think are significant in causing cancer, then we do confirmatory studies to figure out exactly how significant they are. Then the next step is to try to figure out, if we do clinical testing for those genes, what will the impact be? What will we be able to offer these women to decrease their risk of breast cancer? That’s what we did initially with the BRCA genes – we found out that they cause breast cancer, and then we could offer oophorectomies or mastectomies to these women to decrease their risk.

Would you tell me more about the relationship between obesity and breast cancer?
We know that obesity predisposes women to breast cancer, especially later in life. There also have been several studies that show that women who are obese tend to have a worse prognosis when they are diagnosed with breast cancer – they have a higher risk of recurrence. Part of it could be that the chemotherapy doesn’t work as well, part of it could be higher estrogen levels, and a lot of it is unknown.

There’s also a suggestion that women who are diagnosed with breast cancer gain weight. They may gain weight from treatment, they may gain weight because they decide to stop exercising, but they do gain weight. And we know that gaining weight after diagnosis can again lead to a worse prognosis. I’m looking to see what the reasons are for women gaining weight, and if we can predict ahead of time who is going to gain weight and who is not. My ultimate goal is to identify the women who are at a high risk of gaining weight and offer those women exercise programs and nutritional programs, instead of the whole population.

What can people expect from the Lynn Sage Town Hall event?
We’re going to have a range of physicians – two oncologists, one surgeon, one radiation oncologist, and one endocrinologist – who are working in breast cancer at different points and levels. We will each give a presentation about what we work on and what’s coming up in the future as far as our specialty and breast cancer. But we only spend five to ten minutes talking about what we do, and the rest of the time will be open to questions about what people want to know about breast cancer. It’s very interactive. Everyone always comes out learning things, including myself.

The Robert H. Lurie Comprehensive Cancer Center of Northwestern University Lynn Sage Breast Cancer Town Hall event on October 24th is free and open to the public. Visit our events section for time, location, and registration information.

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