Novel Breast Cancer Tumor Suppressor Pathways
Abstract
Background: Important tumor suppressor genes have been characterized in breast cancer. We have discovered that metabolism of the amino acid lysine is a novel tumor suppressor pathway in breast cancer. Expression of the enzyme that catalyzes the amino acid lysine to acetoacetate is significantly reduced in human breast cancer. We demonstrate that overexpression of this enzyme or acetoacetate treatment makes breast cancer cells digest themselves and stop dividing. Acetoacetate inhibits the enzyme lactate dehydrogenase (Ldha) in these cells, and Ldha inhibition also makes breast cancer cells digest themselves and stop dividing. We show that lysine metabolism is regulated by the breast cancer tumor suppressor peroxisome proliferator activated receptor gamma (PPARgamma). PPARgamma binds inflammatory mediators such as fatty acids and alters expression of target genes. PPARgamma uses repressors and activators to modify DNA structure of its target genes. Surprisingly, we identified increased PPARgamma signaling in breast cancers from obese women. Obese women have increased levels of inflammation, which result in elevated risk of breast cancer. We hypothesized that the lysine metabolic pathway may be altered in a PPARgamma-dependent manner in obesity-associated breast cancer. Breast cancer risk and prognosis is worse for obese compared to normal weight women. Using a new model, we showed that aggressive obesity-associated breast cancer was PPARgamma-dependent; deletion of PPARgamma in the mammary gland unexpectedly resulted in increased time to develop cancer and depleted tumor cells in the obese environment. Mammary tumors in the PPARgamma-deficient obese environment exhibited increased lysine metabolism, which resulted in self-digestion and decreased cell division. These results indicate that obesity inhibits PPARgamma tumor suppressor function and lysine metabolism. The overarching challenge of our application is to distinguish these deadly from non-deadly breast cancers. We hypothesize that the lysine metabolic pathway is a new PPARgamma-regulated breast cancer tumor suppressor. The obese environment alters this tumor suppressor pathway, resulting in aggressive breast cancer. Targeted chemotherapy intervention in this pathway will inhibit breast cancer growth and improve clinical outcomes for patients with obesity-related breast cancer. Specific Aim 1 will characterize obesity-mediated regulation of our novel breast cancer metabolic tumor suppressor pathway. Specific Aim 2 will determine the role of the obesity in mediating the effects of our novel breast cancer tumor suppressor pathway. Specific Aim 3 will characterize activation of our novel tumor suppressor pathway using targeted therapies. Study Design: In Specific Aim 1, we will characterize altered target gene interactions and DNA modifications using new preclinical genetic models. We will activate our breast cancer tumor suppressor pathway by altering these DNA modifications. We will determine the effects of activating this pathway on breast cancer using new preclinical models. In Specific Aim 2, we will characterize environmental and cellular effects of obesity on breast cancer using novel preclinical models. We also will determine the role of self-digestion in mediating the effects of our new tumor suppressor pathway in vivo. In Specific Aim 3, we will determine the effects of inhibiting DNA modifiers and Ldha using unique models of breast cancer. We will determine mechanisms underlying these effects using new cutting-edge metabolomics technologies and examine Ldha inhibition by acetoacetate. Impact: We have discovered a new metabolic tumor suppressor pathway that is applicable to most types of human breast cancer, which will significantly contribute to the Breast Cancer Research Program mission of ending breast cancer. Regulation of this pathway using new targeted inhibitors will be more effective against obesity-related breast can
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010029
Entities
People
- David L Crowe
Organizations
- United States Army
- University of Illinois at Chicago