Lay abstracts on BCERP research
Obesity found to be major risk factor in developing basal-like breast cancer
Weight loss reversed obesity-induced HGF/c-Met pathway and basal-like breast cancer progression
Normal breast tissue of obese women is enriched for macrophage markers and macrophage-associated gene expression
Obesity found to be major risk factor in developing basal-like breast cancer
Sneha Sundaram, Alex J. Freemerman, Amy R. Johnson, J. Justin Milner, Kirk K. McNaughton, Joseph A. Galanko, Katharine M. Bendt, David B. Darr, Charles M. Perou, Melissa A. Troester, and Liza Makowski
Obese women face an increased risk of developing the basal-like subtype of breast cancer, according to research conducted at the University of North Carolina.
In a study published online by the journal Breast Cancer Research and Treatment, a team led by Liza Makowski, assistant professor in the Department of Nutrition in the UNC Gillings School of Global Public Health and member of the UNC Lineberger Comprehensive Cancer Center, and Sneha Sundaram, PhD, a post-doctoral fellow in the Makowski Lab, outlined the biological mechanisms where obesity can create a favorable environment for the growth of basal-like breast cancer tumors.
“Obesity is widespread and is one of the few risk factors for breast cancer that we may be able to control, hence our intention in this study was to better understand the molecular mechanisms and/or biomarkers of obesity-related basal like breast cancer that could impact disease prevention,” said Dr. Makowski.
Breast cancer is a heterogeneous disease made up of several distinct subtypes. The basal-like subtype, an aggressive form of breast cancer, is found in 15 to 20 percent of women diagnosed with breast cancer, with a high percentage of cases found among young and African American women. Women diagnosed with the basal-like subtype often have a poor prognosis and cannot be treated with hormonal and targeted therapies.
Using a mouse model developed to study the basal-like subtype, the research team discovered that obesity radically alters the cellular microenvironment of mammary glands in ways favorable to the growth of basal-like tumors. One major change is that obesity promotes a growth factor signaling pathway between the hepatocyte growth factor (HGF) protein and an oncogene known as c-Met that is linked with basal-like cancer formation. In animals with elevated levels of HGF, the development of basal-like tumors increased.
“Our study was fairly unique in that we focused on the role that the surrounding tissue in the breast, known as the stroma, plays in breast cancer onset. Many scientists study the tumor alone, but the stroma ‘soil’ where the cancer ‘seed’ grows is important in helping that tumor grow,” said Makowski.
Since HGF levels are increased with obesity, the study indicates that public health efforts to prevent obesity in at-risk populations may be a clinically useful way of preventing the disease. Makowski said that whether weight loss can minimize breast cancer risk in already obese patients is an area that needs further investigation. Read the full article.
Weight loss reversed obesity-induced HGF/c-Met pathway and basal-like breast cancer progression
Sneha Sundaram, Trinh L. Le, Luma Essaid, Alex J. Freemerman, Megan J. Huang, Joseph A. Galanko, Kirk K. McNaughton, Katharine M. Bendt, David B. Darr, Melissa A. Troester, and Liza Makowski
Population studies suggest that obesity contributes to at least half of an aggressive subtype of breast cancer called basal-like breast cancer (BBC). Obesity is widespread and is one of the few risk factors for breast cancer that we may be able to control. We previously showed that obesity in adult mice drove early onset of BBC tumors which was similar to findings that in humans, BBC often strikes at a young age. In our study, obesity also drove the increase in tumor growth factors including the hepatocyte growth factor (HGF) and its receptor, c-Met in the mammary gland. Thus, we discovered a link between the cancer causing HGF/c-Met pathway and BBC in obesity. Various studies in human populations have suggested therefore that lifestyle intervention including weight loss could prevent a large proportion of BBC. Hence our intention was to better understand if weight loss could lead to decreased tumor growth in mice and to discover the molecular mechanisms associated with obesity and weight loss with the overall goal to prevent or treat BBC. In mice made obese from feeding a high fat diet from an early age, tumors grew rapidly compared to mice that remained lean throughout life. When obese mice were induced to lose weight before tumors developed, tumor growth was slowed to levels similar to lean mice. Proteins that can lead to increased cancer onset and growth were increased by obesity and importantly, decreased with weight loss including the HGF/c-Met pathway, insulin, and the leptin:adiponectin ratio. Our findings suggest that obesity-driven factors such as HGF/cMet, insulin, and the leptin: adiponectin ratio may contribute to the onset of obesity-promoted BBCs and the dramatic reversal of obesity-driven tumor aggressiveness after weight loss. Studies to discover if BBC can be prevented or treated through using drugs to inhibit the HGF pathway are currently ongoing. Taken together, our data demonstrate that obesity-increased tumor growth can be reversed by weight loss even before tumors were detected. Our findings are encouraging and further support maintaining a healthy weight to decrease cancer risk. Read the full article.
Obesity-mediated regulation of HGF/c-Met is associated with reduced basal-like breast cancer latency in parous mice
Sundaram S, Freemerman AJ, Galanko JA, McNaughton KK, Bendt KM, Darr DB, Troester MA, Makowski, L. Obesity-mediated regulation of HGF/c-Met is associated with reduced basal-like breast cancer latency in parous mice.
Basal-like breast cancers (BBCs) lack estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) protein expression, thus are often referred to as “triple-negative” breast cancers, and as such these cancers lack a targeted therapy. In population studies, a full term pregnancy (parity) reduces the risk for estrogen receptor positive (ER+) breast cancers, while parity is associated with increased risk of BBC subtype – but mechanisms remain unknown. Experimental studies have examined parity and obesity individually, but the joint effects of parity and obesity had not been studied. Therefore we investigated the role of obesity in parous mice on BBC. We found that parity alone dramatically decreased time to tumor compared to nulliparous controls – in other words, tumors came on more sooner. Obesity had only a minor role in further reducing time to tumor in parous mice relative to nulliparity. In the normal mammary glands of parous mice, we discovered that c-Met concentrations were 2.5-fold greater with obesity, suggesting a role for the c-Met cancer-driving pathway in BBC risk with pregnancy. It is unclear if pregnancy and obesity in humans drive activation of the same pathway. The best news is that breastfeeding helps reduce risk of BBC, thus maintaining a healthy weight and breastfeeding are important actions to help reduce risk of this aggressive cancer. Read the full article.
