OCT 29, 2014 12:00 PM PDT

Obesity, weight loss, and the microenvironment in basal-like breast cancer

Speaker
  • Assistant Professor, Nutrition, UNC Gillings School of Global Public Health
    Biography
      Liza Makowski is an assistant professor of Nutrition, Division of Nutrition Biochemistry in the Departments of Nutrition and Medicine at the UNC Gillings School of Global Public Health and the UNC School of Medicine. She earned a Ph.D. in the Department of Nutrition at the Harvard School of Public Health and a Masters in Medicine concurrent with her Ph.D. studies as a Lucille P. Markey Fellow from Harvard Medical School. Liza completed postdoctoral studies in the Departments of Medicine and Pharmacology & Cancer Biology at the Duke University Stedman Center for Nutrition and Metabolism. Dr. Makowski has expertise in metabolism, inflammation, mouse models, macrophage biology, and nutrient sensitive signaling pathways. The research focus of the Makowski Lab (http://makowskilab.web.unc.edu/) is to understand metabolic reprogramming of immune cells wherein the goal is to identify novel pathways to manipulate substrate metabolism in immune cells in efforts to limit the pathogenesis of complex diseases such as obesity and diabetes. Dr. Makowski has received multiple grants including a Pathway to Independence NIH K99/R00 award to investigate macrophage mitochondrias role in metabolism and inflammation. She is currently PI on an NIH R21 Provocative Question Grant and a Mary Kay Foundation grant to study obesity and breast cancer risk, and an American Heart Association grant to study substrate metabolism in macrophage biology. Her ultimate aim is to find relevant metabolically sensitive pathways in her model systems, observe parallels in human populations, and identify targets to reprogram immune cells that will restore tissue homeostasis thereby reducing progression of obesity, diabetes, atherosclerosis, and cancer.

    Abstract

    Obesity is associated with an aggressive subtype of breast cancer called basal-like breast cancer (BBC). Using C3(1)-TAg mice, a genetically engineered mouse model that resembles human BBC, we demonstrated that mice displayed increased tumor aggressiveness when fed obesogenic diets. Obesity induced in the adult window of susceptibility triggered early latency and elevated mammary gland expression and activation of hepatocyte growth factor (HGF)/c-Met compared to lean controls, a pro-tumorigenic pathway associated with BBC in patients. HGF secretion was also increased from primary mammary fibroblasts isolated from normal mammary glands and tumors of obese mice compared to lean. Conditioned media from primary tumor fibroblasts from obese mice drove tumor cell proliferation compared to lean controls. In co-culture, neutralization of secreted HGF blunted tumor cell migration, further linking obesity-mediated HGF-dependent effects to in vitro measures of tumor aggressiveness. Using a more severe diet model, we exposed mice to a lifelong diet intervention - C3(1)-TAg mice were weaned onto and maintained on an obesogenic high fat diet. Obese mice displayed significant elevations in tumor progression. Epidemiologic studies estimate that weight loss could prevent a large proportion of BBC. We sought to investigate whether weight loss in adulthood prior to tumor onset would protect mice from the accelerated tumorigenesis observed in obese mice. Indeed, tumor progression was significantly reversed when obese mice were induced to lose weight by switching to a control low fat diet prior to tumor onset compared to mice maintained on obesogenic diet. Obesity-elevated HGF/c-Met expression in normal mammary glands and c-Met in tumors was significantly reversed with weight loss. Other mediators associated with oncogenesis such as hyperinsulinemia and a high leptin/adiponectin ratio were also elevated by obesity and reduced with weight loss. In sum, weight loss significantly blunted the obesity-responsive pro-tumorigenic HGF/c-Met pathway and improved several metabolic risk factors associated with BBC, which together may have contributed to the dramatic reversal of obesity-driven tumor progression. Future research aims to evaluate the role of obesity, the mammary microenvironment, and the HGF/c-Met pathway in basal-like cancer progression.

    Learning Objective:

    • After completing this activity the learner will be able to understand how obesity and weight loss affect the normal mammary gland and tumor in a murine model of basal like breast cancer.
    • Links to human studies and ongoing outreach programs will be discussed.

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    OCT 29, 2014 12:00 PM PDT

    Obesity, weight loss, and the microenvironment in basal-like breast cancer


    Specialty

    Biotechnology

    Cell

    Molecular Biology

    Hepatology

    Cell Culture

    Cancer Research

    Research

    Molecular Diagnostics

    Immunology

    Dna

    Cancer Therapeutics

    Cancer

    Infectious Disease

    Gene Expression

    Cell Biology

    Geography

    Asia100%

    Registration Source

    Website Visitors100%

    Job Title

    Research Scientist100%

    Organization

    Academic Institution100%


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