Event Title

Lysine Metabolism is a New Tumor Suppressor Pathway in Breast Cancer that is Deregulated by Obesity

Session Number

C01

Advisor(s)

David Crowe, University of Illinois at Chicago

Location

B-116

Start Date

28-4-2016 10:40 AM

End Date

28-4-2016 11:05 AM

Disciplines

Biology

Abstract

Obesity (excess fat) is a cause of breast cancer, but reasons for this are not understood. Peroxisome proliferator- activated receptor gamma (PPARɣ) is responsible for fat cell differentiation and is activated by fatty acids stored in fat cells. PPARɣ prevents breast cancer in humans. We hypothesized that excess fatty acids may reverse PPARɣ function to tumor promotion. To test this hypothesis, we deleted the PPARɣ gene in mammary epithelium of normal and obese mice. Decreased PPARɣ expression in obese mice increases tumor latency and depletes tumorigenic progenitor cells. These cells slowly digest their mitochondria by the process of autophagy. To understand this, we determined changes in gene expression in obese PPARɣ null mammary tumors. Gene expression analysis showed a 16-fold increase in 2- aminoadipate semialdehyde synthase, an enzyme involved in lysine catabolism. PPARɣ suppressed expression of this enzyme, which may reduce cellular acetoacetate concentration (the end product of lysine catabolism). Human breast cancer lines that over expressed the synthase or were exposed to increased acetoacetate concentrations showed reduced proliferation and autophagy similar to that observed in mammary tumors. We conclude that obesity changes PPARɣ function from tumor suppressor to tumor promoter by inhibiting lysine catabolism, intracellular acetoacetate levels, and autophagy.


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Apr 28th, 10:40 AM Apr 28th, 11:05 AM

Lysine Metabolism is a New Tumor Suppressor Pathway in Breast Cancer that is Deregulated by Obesity

B-116

Obesity (excess fat) is a cause of breast cancer, but reasons for this are not understood. Peroxisome proliferator- activated receptor gamma (PPARɣ) is responsible for fat cell differentiation and is activated by fatty acids stored in fat cells. PPARɣ prevents breast cancer in humans. We hypothesized that excess fatty acids may reverse PPARɣ function to tumor promotion. To test this hypothesis, we deleted the PPARɣ gene in mammary epithelium of normal and obese mice. Decreased PPARɣ expression in obese mice increases tumor latency and depletes tumorigenic progenitor cells. These cells slowly digest their mitochondria by the process of autophagy. To understand this, we determined changes in gene expression in obese PPARɣ null mammary tumors. Gene expression analysis showed a 16-fold increase in 2- aminoadipate semialdehyde synthase, an enzyme involved in lysine catabolism. PPARɣ suppressed expression of this enzyme, which may reduce cellular acetoacetate concentration (the end product of lysine catabolism). Human breast cancer lines that over expressed the synthase or were exposed to increased acetoacetate concentrations showed reduced proliferation and autophagy similar to that observed in mammary tumors. We conclude that obesity changes PPARɣ function from tumor suppressor to tumor promoter by inhibiting lysine catabolism, intracellular acetoacetate levels, and autophagy.