From new research linking BRCA mutations and DNA damage to the effects of breastfeeding on offspring, three studies presented at ENDO 2018 in Chicago all share a common if not always obvious connection: Obesity is often in the genes, but it is far from inevitable.
Three studies presented at ENDO 2018 in March kept attendees abreast of what is happening in research concerning the mammary gland. One zooms in on the BRCA mutation, and the other two elucidate aspects of breastfeeding. Interestingly, all three are tied together with another common thread — avoiding obesity. Taken together, these studies underscore the importance of maintaining a healthy weight.
Good News for BRCA Mutation Carriers
In “In BRCA mutation carriers, obesity is linked with increased DNA damage in normal breast gland cells,” lead researcher Kristy A. Brown, PhD, and colleagues from Weill Cornell Medicine in New York, N.Y., took a molecular-level look at the tie between obesity and breast cancer development in BRCA mutation carriers, as evidenced in clinical observations.
BRCA mutation, as is well known, means that the carrier’s DNA repair enzymes are faulty, and tumors are not kept in check as they otherwise might be; therefore, these women have an increased risk of breast and ovarian cancer. Brown and team hypothesized that obesity or increased body mass index (BMI) may be associated with higher levels of DNA damage in the normal breast epithelium of carriers. They recruited 82 women who had identified BRCA mutations and generated tissue microarrays, a technique that allows more than 100 different patient samples to be viewed on a single slide. With the microarrays, they used immunofluorescence to stain for gamma-H2AX foci, a histone mark occurring when DNA is damaged. “One of the first observations we made was that BMI was associated with more of these gamma-H2AX foci in breast tissue, which is an indication of higher levels of DNA damage. This is important as it is hypothesized that DNA damage can lead to tumor formation if not properly repaired,” Brown says.
An additional arm of the study involved determining whether a relationship existed between this DNA damage and previously characterized players in the obesity–breast cancer link, the estrogen biosynthetic enzyme, aromatase, as well as crown-like structures, which are inflammatory foci also found in the breast. “We found a positive correlation between these two factors and the formation of DNA damage foci. We are currently undertaking additional studies to be able to establish causation,” Brown says.
They also used an animal model of obesity to see whether obesity alone would be sufficient to cause this effect. After feeding formerly cancer-free mice a high-fat diet, the researchers assessed the amount of DNA damage in the mouse mammary glands.
“What we found was similar to the studies in the BRCA mutation carriers–there was an increase in DNA damage in the normal mammary gland of the mice,” Brown explains. “What becomes more interesting is that after we submitted these mice to caloric restrictions, we saw reduction in the number of these focal points, suggesting that DNA damage may be preventable or even reversible.”
Many more studies will be needed to confirm this idea, but these results are encouraging, perhaps even empowering, for carriers nonetheless. In women with the mutation for whom cancer development is highly probable, maintaining a healthy lifestyle and a healthy BMI becomes critical in order to limit exposure to factors that have negative effects in the breast. “Through diet and exercise, women in that population may be able to reduce their risk of breast cancer, which is supported by a seminal study by Mary-Claire King, published in Science in 2003, which showed that avoiding obesity decreases the penetrance of breast cancer in BRCA mutation carriers.”
“…other problems come along with early puberty, like glucose disruption, which is an indicator for prediabetes. We think our findings to some extent can alert endocrinologists and their patients with early puberty to watch for other health problems after they become adults.” – Mengjie Wang, MD, MS, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
The team is very much interested in causation and will be investigating whether obesity-associated factors may be responsible for the increase in DNA damage as well as whether that leads to tumor formation. “The current study is really a first look at what’s happening to the DNA,” Brown says. “Which factors are involved and whether there is a way to intervene is part of ongoing studies.”
Large-for-Gestational Age Children May Gain Advantage from Breastfeeding
In “Breastfeeding may protect high-birthweight infants from childhood obesity,” lead researcher Hae Soon Kim, MD, of Ewha Womans University College of Medicine in Seoul, South Korea and team studied 38,039 children in three groups — low birthweight (≤2,500 grams), normal birthweight (2,500–4,000 grams), and high birthweight (≥4,000 grams) — starting from birth and evaluating their growth development in relation to their birthweight at regular checkpoints.
When the cohort reached age six years, the researchers found that 10% of the low-birthweight group, 15% of the normal-birthweight group, and more than 25% of the high-birthweight group had become obese or overweight (pediatric criteria for obesity in South Korea is a BMI of ≥95th percentile for age and sex). However, the risk of obesity was considerably lower when the high-birthweight children were exclusively breastfed during their first six months.
With pediatric obesity now so prevalent, this newly demonstrated benefit of breastfeeding may provide more mothers food for thought.
Breastfeeding Mothers: Avoid Fatty Foods
In “Overeating during breastfeeding may affect the health of offspring,” principal investigator Jennifer W. Hill, PhD, and graduate research assistant Mengjie Wang, MD, MS, at the University of Toledo College of Medicine and Life Sciences in Ohio, sought answers on what factors may account for the global penetrance of early puberty. Looking at previous studies, the researchers found childhood obesity commonly cited as a comorbidity; not surprisingly, both of these conditions have increased in incidence around the world. “Epidemiological evidence shows that from 1970 to now, puberty is beginning one year earlier than before. Normally, in girls, it should be 10 to 12 years old, but now early puberty is defined in girls before [they are] eight years old. And, some believe we need additional diagnostic criteria for people for different regions, so, it may be even earlier than that,” Wang says.
The team also knew from a 2014 animal study from the lab of Jens Brüning that a maternal high-fat diet and overeating can affect timing of puberty, in which they figured out that the breastfeeding phase from the date of birth to the weaning date is the most critical window for metabolic functions in the offspring. “Our ideas came from that paper,” Wang says. “We want to understand how maternal high-fat diet feeding only during the breastfeeding phase can regulate metabolic and reproductive function in the offspring.”
To determine how excess body weight may alter the timing of puberty, they used two groups of C57/BL6 mice, a control group of new mothers and a group who were fed high-fat food (60% of calories from fat) from the date they delivered to weaning. They checked body weight of the offspring every week from week 3 to week 20. To evaluate pubertal development in female mice, they used vagina opening and the first estrous age as markers. “We found that the excess calories during the breastfeeding phase can cause early obesity due to increased fat mass and we also found earlier puberty in those mice,” Wang says. Furthermore, glucose tolerance tests showed glucose intolerance and insulin insensitivity. Finally, performing fertility tests of the offspring in adulthood demonstrated such infertility problems as smaller litters, longer times to become pregnant, and lower pregnancy rates.
“What we found was similar to the studies in the BRCA mutation carriers–there was an increase in DNA damage in the normal mammary gland of the mice. What becomes more interesting is that after we submitted these mice to caloric restrictions, we saw reduction in the number of these focal points, suggesting that DNA damage may be preventable or even reversible.” – Kristy A. Brown, PhD, Weill Cornell Medicine, New York, N.Y.
In the future, Wang and her team plan to pursue such mechanisms as how a maternal high-fat diet might change the microbiota of the offspring and how, in turn, those changes might influence their pubertal development.
The jury is out as to whether these results apply to humans. However, we can provisionally extrapolate some implications, according to Wang. “The first thing I would want to tell a clinician is that a maternal high-calorie diet does advance puberty, so advise your patients to avoid excess calories,” she explains. “Second, other problems come along with early puberty, like glucose disruption, which is an indicator for prediabetes. We think our findings to some extent can alert endocrinologists and their patients with early puberty to watch for other health problems after they become adults.”
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