Obesity and Breast Cancer Spread Focus of New ICRF Project Grant

Obese women have a higher risk of developing breast tumors that are resistant to therapies, and once diagnosed, they have worse clinical outcomes, as cancer is more likely to recur and is associated with higher death rates. Professor Michael Elkin, an earlier recipient of an ICRF Research Career Development Award, has received a Project Grant to explore aspects of obesity-associated breast cancer progression.

Your research on the progression of cancer in overweight women was recently published in the prestigious Cancer Research. Can you describe your recent significant breakthrough?

Our research, published in Cancer Research, identified heparanase enzyme as a mechanistic determinant of the link between obesity and hormone responsive breast cancer. However, it  is important to note that the association between obesity and the increased risk of hormone responsive breast carcinoma in post-menopausal women has been demonstrated in earlier studies. In addition, it has been shown that once diagnosed, obese patients bearing hormone responsive breast tumors have worse clinical outcomes (i.e., in obese patients,  cancer manifests itself more aggressively and treatments are often less effective). Yet, mechanistic aspects of obesity-breast cancer link were not fully elucidated.

Our findings may help to understand the mechanism underlying the causative link between obesity and hormone-responsive breast cancer development. Briefly, we found that the enzyme called heparanase orchestrates a complex multi-site molecular program, which occurs concurrently in adipose and breast tumor tissues, and sustains obesity-accelerated breast carcinoma progression through enhanced action of hormone estrogen. Heparanase is a unique enzyme that had been cloned/characterized by Professor Israel Vlodavsky (recipient of numerous ICRF awards, including an ICRF Research Professorship and my PhD mentor more than 20 years ago). This enzyme plays a central role in cancer progression. We found that heparanase is overexpressed in clinical and experimental obesity-associated breast tumors. Moreover, deficiency of the enzyme abolished the tumor-promoting action of obesity in mouse models; in mice lacking the enzyme heparanase, obesity had no effect at all on tumor development. Collectively, our study defined heparanase as a marker of obesity-related breast carcinoma progression and provided a molecular explanation for accelerated growth of hormone-responsive breast tumors under obese state.  Given ongoing development of heparanase inhibiting compounds, our study may offer a mechanistically informed approach to uncouple obesity and breast cancer in a rapidly growing population of obese patients, and to suppress the breast cancer-promoting consequences of excess adiposity. This has the potential of offering clinical benefit for breast cancer patients with elevated body weight.

Can you share your views on the importance of a healthy diet and exercise as a preventative?

 At least for 14 cancer types, obesity is regarded as one of the main preventable causes. Based on what I see reported in scientific literature during the last decade, along with observations made by our research group (which are limited to murine models of obesity-related breast cancer  and mainly related to cancer-promoting action of high-fat diet and other obesogenic substances, such as advanced glycation end products), I think that any medical/behavioral action aimed at reducing obesity (including healthy diet, physical activity and according to some reports, weight-loss surgery) could be considered as a preventative and may lower the future risk of obesity-related breast cancer.

How has ICRF impacted your work?

ICRF support has had a major impact on my work. During the earlier phase of my career (2006-2015), it was ICRF support (including the Research Career Development Award) that enabled us to conduct studies on pancreatic cancer. Today, almost ten years later, our current ICRF Project Grant has enabled our team to enter a new and exciting area of research – exploration of the mechanistic aspects of obesity-associated breast cancer progression. 

ICRF is currently supporting nine projects in the area of breast cancer research:

Michael Elkin, PhD, a recipient of an ICRF Project Grant at Hebrew University-Hadassah Medical Center, is studying the link between obesity and breast cancer. Obesity is associated with metabolic endotoxemia – the chronic presence of extremely low, but biologically significant, levels of bacterial endotoxin. Dr. Elkin believes that the continued presence of subclinical levels of bacterial endotoxin aids in the formation of breast cancer cells. His team will test this hypothesis, using newly-established experimental tools, in animal models and clinical samples.

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