Breast Cancer: Elevated BMI causes more DNA damage in breast cells

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Breast Cancer: Elevated BMI causes more DNA damage in breast cells

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Breast Cancer: Elevated BMI causes more DNA damage in breast cells.

The Cornell researchers found that elevated BMI causes more DNA damage in breast cells and increases the risk of breast cancer!

Obesity (body mass index (BMI) ≥ 30), is an established risk factor for breast cancer in postmenopausal women in the general population. However, epidemiological studies have been inconsistent as to whether elevated BMI is a risk factor for women with BRCA1 or BRCA2 germline mutations.

Recently, a research team led by Priya Bhardwaj of Weill Cornell Medical College published a study titled “Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in BRCA1 or BRCA2” in Science Translational Medicine .

The study found that among women with BRCA gene mutations, having a high body mass index (BMI) was associated with more DNA damage in breast cells .

DOI: 10.1126/scitranslmed.ade1857

Specifically, the study found that higher BMI was associated with greater DNA damage in epithelial tissue.

They also found a link between this impairment and increased estrogen, as well as hormones associated with obesity, such as leptin and insulin .

Research Background

The BRCA1 and BRCA2 genes are a dynamic combination, and each person has a different version. BRCA genes work together to protect people from certain cancers by promoting mutation-free cell division and repairing DNA damage in cells .

Effectively preventing damaged cells from replicating errors can prevent the formation of cancerous tumors. Mutations in these genes are often associated with, and named after, breast cancer.

There are thousands of variants of BRCA, most of which do a good job of repairing DNA and keeping us from tumors.

However, certain variants of these genes increase the risk of repair errors .

A failed DNA repair job can quickly turn into a mutated cell with incomplete signaling genes, causing the mutated tissue to eat uncontrollably, ignore the demands of surrounding tissue to stop growing, become a tumor, and be diagnosed as cancer.

Obesity (body mass index (BMI) ≥30), is an established risk factor for breast cancer in women in the postmenopausal general population.

However, epidemiological studies have been inconsistent on whether elevated BMI is a risk factor for women with BRCA1 or BRCA2 germline mutations, and mechanistic studies in this population are currently lacking.

Elevated BMI increases breast DNA damage

For the study, the team analyzed cultured healthy breast tissue collected from 69 individuals with mutations in the BRCA1 and BRCA2 genes.

Samples were classified as coming from lower body weight (BMI < 25 kg/m2, n = 43) and overweight/obese (BMI ≥ 25.0 kg/m2, n = 26).

Individuals with higher BMIs had increased DNA damage , the results showed .

DNA damage in the normal breast epithelium of women with BRCA mutations was positively associated with BMI and biomarkers of metabolic dysfunction .

RNA-sequencing revealed that obesity-associated alterations in the breast fat microenvironment in BRCA mutation carriers, including activation of estrogen biosynthesis, affected adjacent mammary epithelial cells .

In addition, the study conducted an ancillary mouse experiment. Two groups of mice were fed a high-fat or low-fat diet for 28 weeks.

High-fat-fed mice had more mammary DNA damage than low-fat-fed mice. At the end of the monitoring period, the high-fat feeding group was 16.5 percent more likely to develop breast tumors.

In the lab, they found that they could reduce the effect of elevated BMI on DNA damage in epithelial cells by blocking estrogen biosynthesis or blunting estrogen receptor activity with the drug fulvestrant .

The researchers also found that inhibiting leptin and insulin signaling in tissues reduced DNA damage, illustrating a potential causal link between obesity, hormone activity, and epithelial DNA health.

Because damaged DNA is already known to be a causal factor in cancer development, this study highlights an important risk accelerator and hints at potential drug mitigation.

Reduce the risk of breast cancer in high-risk groups

The study, led by Bhardwaj, shows that, in addition to the possible poor repair efforts associated with cancer-associated BRCA variants, people with elevated BMI are at greater risk of needing repair due to increased damage mechanisms.

Maintaining a low body weight, or pharmacologically targeting estrogen or metabolic dysfunction, may reduce breast cancer risk in high-risk groups, the researchers suggest .

References:

https://medicalxpress.com/news/2023-02-breast-cancer-fighting-gene-job-difficult.html

Breast Cancer: Elevated BMI causes more DNA damage in breast cells.

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