Obesity May Increase Breast Cancer Risk Even More in Women With BRCA Mutations
Obesity may lead to DNA damage in the milk glands of women with a BRCA1 or BRCA2 mutation, which may increase the risk of developing breast cancer even more in this already high-risk group.
The research was published in the Feb. 22, 2023, issue of the journal Science Translational Medicine. Read the abstract of “Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in BRCA1 or BRCA2.”
About BRCA mutations
Genes are short segments of DNA (deoxyribonucleic acid) found in chromosomes. DNA contains the instructions for building proteins. And proteins control the structure and function of all the cells that make up your body.
Think of your genes as an instruction manual for cell growth and function. Changes or mistakes — called mutations by scientists — in the DNA are like typographical errors. They may provide the wrong set of instructions, leading to faulty cell growth or function. When there is a mutation in a gene, that same mutation appears in all the cells that contain the same gene. It’s like having an instruction manual in which all the copies have the same typographical error.
There are two types of DNA changes: those that are inherited and those that happen over time. Inherited DNA changes are passed down from parent to child. Inherited DNA changes are called germline mutations.
DNA changes that happen over the course of a lifetime — as a result of the natural aging process or exposure to chemicals in the environment — are called somatic mutations.
About 5% to 10% of breast cancers are thought to be the results of germline mutations.
Two of the most well-known genes that can mutate and raise the risk of breast and ovarian cancer are BRCA1 and BRCA2. Women who inherit a mutation in either of these genes — from their mothers or fathers — have a much higher-than-average risk of developing breast cancer and ovarian cancer.
Obesity and breast cancer risk
Women who are considered overweight or obese — defined as having a BMI (body mass index) of 25 or more — have a higher risk of being diagnosed with hormone receptor-positive breast cancer than women who maintain a healthy weight, especially after menopause. Being overweight also can increase the risk of the breast cancer coming back (recurrence) in women who have had the disease.
This higher risk is because fat cells make estrogen; extra fat cells mean more estrogen in the body, and estrogen can make hormone receptor-positive breast cancers develop and grow.
Still, the link between extra weight and breast cancer is complicated and affected by other factors. For example, the location of the extra weight matters. Extra fat around your belly may increase risk more than the same amount of extra fat around your thighs or hips.
About the study
In this study, the researchers wanted to see if obesity was linked to an even higher risk of breast cancer in women with a BRCA1 or BRCA2 mutation because earlier studies have offered conflicting results.
The researchers analyzed healthy samples of milk gland tissue from 69 women with either a BRCA1 or BRCA2 mutation who had mastectomy:
40 women had a BRCA1 mutation
29 women had a BRCA2 mutation
The women’s BMIs were between 19.38 and 44.9.
Overall, 43.5% of the women had been diagnosed with invasive breast cancer:
41.9% of women with a BMI lower than 25 had invasive breast cancer
46.2% of women with a BMI of 25 or greater had invasive breast cancer
Women with a BMI of 25 or greater were also more likely to have high cholesterol and high blood pressure.
The researchers looked at the breast tissue samples with a fluorescence microscope using a technique called immunofluorescence to analyze the components in the tissue. They found that women with a higher BMI had more DNA damage in their tissue samples.
The analysis showed that the hormones leptin, insulin, and estrogen were driving the DNA damage.
Many people who are overweight or obese are also insulin resistant. Insulin regulates your blood sugar (glucose) levels. If you’re insulin resistant, it means your cells stop responding to insulin and your pancreas keeps making more insulin to try to get the cells to respond. But eventually, the pancreas can’t make enough insulin and your blood sugar levels get very high. High blood sugar levels damage the body and can lead to type 2 diabetes.
Leptin is a hormone released by fat tissue to regulate the balance between your food intake and how much energy your body uses. The leptin levels in your body are directly related to how much body fat you have. Leptin resistance makes you feel hungry and eat more even though your body has enough fat to provide the energy it needs.
Fat cells make estrogen, so people with more body fat have more estrogen in the body.
The researchers then checked to see if there were ways to decrease the DNA damage in the breast tissue. Exposing the breast cells to metformin, a medicine commonly used to manage diabetes that lowers blood sugar levels, reduced DNA damage.
Metformin works to lower blood sugar levels in several different ways, including lowering levels of aromatase, an enzyme that helps the body produce estrogen. Using similar mechanisms, medicines called aromatase inhibitors are used to treat hormone receptor-positive breast cancer. They work by stopping aromatase from changing other hormones into estrogen.
In addition to looking at breast tissue samples, the researchers also studied mice with BRCA1 mutations to see if more DNA damage was linked to the growth of cancer tumors. They found that obese mice with metabolic dysfunction — including insulin resistance, high blood pressure, and high cholesterol — developed cancer tumors earlier and had more cancer tumors than lean mice.
The researchers said the results lay the groundwork for future studies looking at whether medicines such as metformin can help lower breast cancer risk in overweight and obese women with a BRCA mutation.
What this means for you
If you have a BRCA1 or BRCA2 mutation and are considered overweight or obese, the results of this study, which suggest extra weight makes your above-average risk of developing breast cancer even higher, are troubling.
Losing weight can be hard, but as this study and others strongly suggest, it can be very important for your health.
Whether or not you’ve been diagnosed with breast cancer, try to make exercise and a healthy diet part of your daily routine. It may be hard to make these kinds of changes if you’re recovering from treatment. Some women say it helps to think of eating well and exercising as important parts of their treatment plans.
Other research suggests that it may be easier to make diet and exercise changes if you have someone to talk to you and motivate you. You might want to talk to your doctor or a registered dietitian about developing a healthy eating plan designed specifically for you and your needs.
It’s also a good idea to talk to your primary care doctor before you start an exercise program. Tell them the exercises you plan to do, and ask if there are any movements you should avoid or if you should limit your range of motion in any way. It’s also smart to talk about any other medical conditions you might have (asthma or osteoporosis, for example) and how they may affect your ability to exercise.
Losing weight is possible with careful diet and exercise changes. Be nice to yourself; don’t punish yourself.
Learn more about exercise and diet and nutrition.
Updated on May 25, 2023