Using mouse models, researchers at the University of California in Davis, California have found evidence that metabolic dysregulation induced by dietary factors can stimulate breast growth and confer breast cancer risk. The data also suggests that this mechanism is independent of estrogen levels, which are viewed as the main driver of female reproductive development. The results are published online in the Proceedings of the National Academy of Sciences.
“Our results in mice at least suggest that other changes in whole body metabolism, which we know is greatly affected by what we eat, can also stimulate breast growth,” said Russell C. Hovey, associate professor of animal science at UC Davis, and one of the authors of the study. “Of course, if there are other things that predispose a woman to breast cancer risk, such as genetics, then this diet-induced effect could superimpose on this and perhaps stimulate precancer cells to grow.”
In contrast to the view that estrogen, which is supplied by the ovaries, initiates breast growth during puberty, this study suggests that diet and metabolism stimulate breast growth independent of the ovaries.
The current view is that breast cancer risk across a woman’s lifetime depends on many internal and external factors, some of which are still unknown. This current study begins to link diet in early life with breast cancer risk later in life. Various epidemiological studies suggest that breast development is sensitive to environmental risk factors before the onset of puberty, including body mass index, diet, obesity, and age of first menstruation.
“We have a lot of epidemiological hints that there is a link between factors such as diet, fat intake, obesity, type 2 diabetes and breast cancer risk, yet it is a complex system when one looks at the whole body level,” explained Hovey. The major impetus for the study was the big question of exactly how does dietary fat intake influence breast development, said Hovey.
The researchers were able to mimic metabolic changes by feeding mice a diet rich in trans-10, cis-12 isomer conjugated linoleic acid (CLA). This type of conjugated fatty acid can disrupt normal metabolic processes and mimic the effect of a metabolic syndrome and obesity-related hypertriglyceridemia, and increase the risk for type 2 diabetes and cardiovascular disease. “Adding this type of fatty acid does not lead to obesity, in fact, the opposite,” said Hovey.
Mice fed a diet rich in this conjugated fatty acid had increased mammary gland stimulation. Surprising to the researchers, the growth was stimulated even in the absence of estrogen (in mice that lacked ovaries). Reversing the metabolic dysregulation by sensitizing the mice to insulin with rosiglitazone(Drug information on rosiglitazone), disrupted the diet-induced mammary gland growth.
“We posit that dietary 10,12 CLA confers its effects on the mammary gland by inducing aspects of the metabolic syndrome that have been repeatedly linked to increased breast cancer risk concurrent with the obesity epidemic, particularly via its effects in young girls,” conclude the authors.
“In my view, this is the first direct experimental evidence that lipids have an estrogenic-type effect on the mammary gland,” said study coauthor Robert D. Cardiff, MD, PhD, of the Center for Comparative Medicine at UC Davis.
The study also found evidence for genetic components that influence the body’s response to diet. Different mouse strains, fed the same linoleic acid supplement had different reactions in terms of mammary gland growth but similar metabolic changes.
According to Hovey, these results can facilitate understanding breast development in humans when estrogen is not present—during childhood and after menopause.
Evidence of the link of diet to cancer already exists. Postmenopausal women with high insulin levels are at higher risk for breast cancer and breast cancer patients who are also diabetic tend to have a poorer prognosis.
“There is a lot of epidemiological data about dietary fat and mammary gland,” said Dr. Cardiff. “However, [lead author Grace E. Berryhill] did a well-controlled experiment that provides direct proof.”
The current findings will likely stimulate more research to understand why girls are experiencing earlier breast development and the link with childhood obesity. CLA—a conjugated fatty acid—is found in dairy products and meat. There is mixed evidence on the benefits and adverse effects of these fatty acids. There is evidence that these molecules have anti-inflammatory effects, including prevention of inflammatory bowel disease, and may reduce the risk of colon cancer. However, CLA has also been shown to enhance insulin resistance in overweight people, increasing the risk of diabetes.
What are other dietary factors that can lead to the same metabolic changes seen in this study? Hovey believes it is any component that can induce the metabolic syndrome and insulin resistance, or excess caloric intake, but much more research is needed on this front.
Future studies are also needed to fully understand how dietary intakes earlier in life influence the body and cancer risk—and if the effect is the same in humans as was seen in mice.
Hovey highlighted the need for continued basic biological research to understand fundamental processes. “This research is one of those biological findings that we think changes the way we think of breast cancer,” said Hovey. “Over the past years it has been set in stone that the normal breast requires estrogen to develop, so we have based a lot of our studies of cancer on this premise. We need to understand normal biology before we fully understand cancer. Now we may need to go back and think a little more about how we assume cancer arises, progresses, and develops.”