Israeli Study Finds How Obesity Can Increase Breast Cancer Rates

Theory maps out previously unknown molecular mechanism that regulates both so-called ‘cancer genes’ and other genes that suppress cancer

The link between obesity and cancer
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Cancer is not a single disease and doesn’t have a single cause, but there are certain factors that increase cancer risk. Some are inherited, some environmental, some chemical and some involve physiological changes. Smoking and air pollution jack up cancer rates, as does insomnia, which has been associated with a range of malignancies, apparently because sleep deprivation weakens the immune system.

Obesity has been associated with multiple types of cancer — but how  and why have remained a mystery. Now, a paper published in the BMC Cancer journal this month describes a novel mechanism by which obesity can increase breast cancer rates.

The study by Dr. Ari Meerson of the Migal Galilee Research Institute (affiliated with Tel-Hai College), local colleagues and researchers at Exeter University in Britain with the lab of Prof. Lorna Harries, was done on post-menopausal women with breast cancer with a wide range of body weight.

Their findings map out a previously unknown molecular mechanism, that involves a regulatory molecule called microRNA, or for short miRNA; the specific culprit is a microRNA called miR-10b.

This short RNA molecule is involved in regulating both oncogenes (genes that can promote cancer) and tumor suppressors (genes that suppress cancer development).

"There have been ideas for the mechanisms of how obesity leads to cancer, but not enough mechanistic understanding. We have shown one specific mechanism. We don't claim it's the only one," Meerson qualifies to Haaretz.

When oncogenes mutate

Our DNA genome consists of genes, regulatory sequences, repetitive and other sequences. (most of it is actually the latter). In the classic understanding, a given DNA gene is translated into an RNA which is then translated into a specific protein. Some RNA types are not translated into proteins but perform various biological tasks as RNAs; among them are microRNAs.

Every protein has one or more specific functions, which may be crucial to the cell and organism, somewhat less crucial, and so on. Some genes and their proteins are so essential to the organism that if the gene mutates, the organism can’t survive (ubiquitin comes to mind).

These genes are present in similar form in many animal species, and therefore are called "evolutionarily conserved" genes.

So, the presence of mutations in a gene, for whatever reason — tobacco, sunlight, alcohol, heredity — the chances are that the protein produced from it won’t work properly, or at all. If the gene is involved in cellular regulation, mutation can cause cells to multiply uncontrollably – which sets the stage for cancer.

Cancer begins when a key gene or set of genes mutate, resulting in abnormal or dysfunctional protein or proteins, dysfunctional regulation, etc. Typically, oncogenes will be activated and tumor suppressors deactivated (mutated or deleted) in a tumor.

As said, cancer exists in numerous forms and a single element, such as chronic alcohol consumption, can lead to a terrifying range of malignant diseases, including of the lungs and upper digestive tract, the liver, colon, rectum, and breast. Obesity is another such factor, and it turns out to be a matter of how genetic expression is regulated.

A versatile regulator

For all the remarkable advances in our understanding of genetics and the increasing ease in sequencing of whole genomes, regulation of gene expression remains a complex problem. What turns genes on and off, and to what magnitude?  By now we do know that microRNAs are an important part of the answer.

MicroRNAs are a large family of short RNA molecules that are not translated into protein; they are involved in regulation of biological processes, cellular regulation and are often implicated in mechanisms of disease.

In this study, the researchers set out to test the hypothesis that microRNAs somehow links between obesity and breast cancer. And they did identify five microRNAs that are expressed differently in normal tissue and cancer tissue.

But only in the case of a microRNA called miR-10b, was the expression in the tumors affected by obesity. Looking at 83 women, the fatter the woman, stronger the drop in level of miR-10b in the tumor. (No, they didn't test breast cancer in men, which is a thing, but a rare thing. So there weren’t any male patients in the sample, Meerson explains.)

MiR-10b is involved in regulating both “cancer genes” and tumor suppressors, which do things like halt cellular division when the DNA is damaged.

MiR-10b is also a highly conserved molecule, suggesting that it is important in normal development. The study showed that suppressing the expression of MiR-10b in cultured breast cancer cells significantly increased cellular proliferation.

The study suggests that the production of miR-10b in our cells may have diagnostic and therapeutic implications for the incidence and prognosis of breast cancer, but medical application of any of this is a very long way off.

But how does obesity lead to change in expression of miR-10b? "We have new unpublished data" says Meerson – “that suggests that it is chronic inflammation, from which obese people are known to suffer, that controls the levels of miR-10b . We are looking forward to publishing these new findings soon.”

That just goes to show how diverse cancer is. Insomnia, parasomnia and sleep apnea are all associated with higher specific cancer rates - apnea for instance is associated with a higher rate of oral cancer. Even mere upset of the circadian clock, i.e., working night shifts, has been linked with increased cancer rates, including breast cancer. 

What does insomnia do to us? A lot: "The lack of high-quality sleep over a long period of time causes anxiety, fatigue, pessimism, and other mental problems," according to a 2018 study in the Medical Science Monitor. "Studies have revealed that lack of sleep can result in abnormal hormone secretion, weakened immunity, neuroendocrine disorders, hypersecretion of angiotensin II, and in high blood pressure." And, yes, chronic insomnia can lead to inflammation. There it is again.