As obesity numbers rise, diseases associated with “dysregulated metabolism” are sure to see their numbers rise as well. New research provides even more causal links between obesity and breast cancer.
With the epidemiological evidence accumulating that obesity not only causes all of the sequelae of metabolic syndrome but also increases the risk of several cancers, research into what links obesity and cancer has revealed startling discoveries and turned what was long held to be a foregone conclusion on its head. This research becomes all the more critical with the explosion of obesity incidence.
Two of the frontrunners of this research, Evan Simpson PhD, FAA, FRSE, and Kristy A. Brown, PhD, both of MIMR-PHI Institute of Medical Research, in Clayton, Australia, and Monash University in Melbourne, and their team have focused specifically on breast cancer in the context of obesity. “Our interest has been primarily the role of local estrogen production in breast cancer in postmenopausal women,” Simpson says. Most postmenopausal breast cancers are estrogen-receptor positive, despite the ovaries having ceased to function in menopause. Simpson and colleagues set out to determine whence the estrogen originates: “The answer is, it’s made in a lot of extraglandular sites, but by far the largest of these is the adipose tissue. Because obese people have more adipose tissue, this becomes a growing source of estrogens in postmenopausal women who have a body mass index greater than 30.”
With local estrogen production within breast fat as a first clue to the relationship between obesity and breast cancer, the team started from the point of view that not only is obesity an example of dysregulated metabolism (in fact, the most prevalent example among humans), but it is also now recognized as a low-grade infl ammatory condition. In “Obesity and Breast Cancer: A Tale of Infl ammation and Aromatase,” published in Molecular Endocrinology, they uncovered how infl ammatory mediators, such as prostaglandin E2 (PGE2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα), etc., stimulate aromatase, the enzyme responsible for estrogen biosynthesis expression in fi broblast tissue. “The inflammation was one component; the other was the dysregulated metabolism,” Simpson says.
“Knowing that the anti-diabetic drug metformin has been shown in a number of epidemiological studies to be protective of a number of cancers including breast cancers, we asked ourselves, ‘how does metformin work?’.” It acts by stimulating 5’ adenosine monophosphate–activate protein kinase (AMPK), which is both an important mediator of many metabolic conditions as well as a master regulator of energy homeostasis. “As we anticipated, we found that AMPK inhibits aromatase expression in the breast and, therefore, estrogen production within the breast,” he says.
They also found that AMPK is associated with other factors involved in obesity such as the adipokines leptin and adiponectin. Leptin, synthesized in adipocytes and, therefore, increased in obesity, stimulates aromatase expression (and consequently increases estrogen production within the breast). Although adiponectin is produced in the adipose tissue, paradoxically, its expression is inversely proportional to the degree of adiposity. Adiponectin levels also inversely correlate with breast cancer risk.
“Our work and that of others demonstrates that obesity leads to an increase in estrogen production in the breast fat. Th is is particularly relevant in older women who are at increased risk of developing hormone-dependent breast cancer in the absence of ovarian estrogens,” Brown says. Support for this explanation has come from studies by Dannenberg’s group at Weill Cornell Medical College and Memorial Sloane Kettering who showed that in the breast fat of obese women, aromatase expression correlates with the production of PGE2, an infl ammatory mediator (“Increased levels of COX-2 and prostaglandin E2 contribute to elevated aromatase expression in infl amed breast tissue of obese women”). “So it all ties in very nicely with the concept that this is a very important problem in postmenopausal women who are overweight,” Simpson says.
Metabolism at the Wheel
Once the “big deal” in biochemistry, metabolism research lost ground to molecular biology and recombinant DNA technology about 20 years ago, Simpson explains. “But in the last decade or so, with the development of techniques to study the regulation of metabolism, suddenly it has leapt to the front again. It used to be thought that metabolism will follow from cell proliferation and cell growth because it is required to supply the other precursors for cell growth like amino acids, purines, pyrimidines, lipids, etc., but now we have realized that you have to turn it the other way around: Metabolism is actually recognized to be a driver of cell growth and proliferation,” he says. In fact, in the article “Hallmarks of Cancer: The Next Generation” published in Cell, Hanahan and Weinberg reported that reprogramming of energy metabolism must be added to the list of the hallmarks of cancer, of which there are currently six as of 2011. “So obesity is one example of dysregulated metabolism in this context,” Simpson says.
The Bad News and the Good News
“With a dramatic rise in the prevalence of obesity over the last few decades, we can expect to see many more cases of breast cancer as this population ages,” Brown says. “But the identification of dysregulated metabolism as a key driver of estrogen biosynthesis within the breast also opens the door to new avenues of treatment for obese women.”
The obvious contender is metformin, which some evidence suggests could potentially be used as breast cancer treatment. “There are now many epidemiological studies being undertaken to determine whether metformin really is beneficial in the context of breast cancer from both the preventative standpoint and the neoadjuvant and adjuvant standpoints. What we have done is point out a major mechanism whereby this applies, namely by stimulating AMPK, which inhibits expression of aromatase,” Simpson says. However, metformin stimulates AMPK via an indirect mechanism, and exactly how has not been fully elucidated. Developing specific agonists to stimulate AMPK is problematic because of its several isoforms and because it consists of a number of different subunits, which are expressed in a differential fashion in different tissues. “To actually nail down one that would be stimulated by a particular drug for all purposes is proving to be a bit of a problem, but people are working on it,” Simpson says.
And for the really good news, studies of resveratrol have shown that it inhibits both breast cancer cell growth in an AMPK-dependent manner and aromatase expression. Glass of red, anyone?
— Horvath is a freelance writer based in Baltimore, Md. She wrote about erectile dysfunction in the December issue.