The Role of Adipocytes in the Tumor Microenvironment in Obesity-Driven Breast Cancer Progression

Author

Sarah Ackerman

Date of Award

2020

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Cohen Paul Laboratory

Abstract

Obesity affects more than 1 in 3 adults in the United States and has been shown to increase the relative risk of death for women with breast cancer and to increase the risk of developing breast cancer in post-menopausal women. Breast cancer develops in an environment containing white adipose tissue (WAT) which predominately consists of mature white adipocytes. In obesity, WAT undergoes hypertrophy and hyperplasia and can ultimately develop hypoxia, insulin resistance, inflammation, and dysregulated endocrine function. Since obesity directly affects WAT, we hypothesized that molecular changes in white adipocytes in the tumor microenvironment contribute to breast cancer progression. We developed mouse models of obesity-driven breast cancer using diet induced obesity (DIO) and orthotopic models of breast cancer. From one of these models, we performed RNA sequencing of peritumoral mammary fat pads and uninvolved contralateral fat pads. Pathway analysis showed an upregulation in transcripts involved in polyamine and creatine biosynthesis in the obese tumor microenvironment. We have found that the rate limiting enzyme in creatine synthesis, Gatm, is upregulated in adipocytes in the tumor microenvironment of obese mice and plays a key role in breast tumor progression. Using an adipocyte-specific knockout of Gatm (Adipo-Gatm KO), we found a significant reduction in obesity-driven breast tumor growth relative to littermate controls. We have also found that knocking down the creatine transporter (Slc6a8) in breast cancer cells fully attenuates obesitydriven tumor progression. These data support a central role for creatine metabolism in breast tumor progression in mice and suggest that adipocyte-derived creatine is utilized by the tumor to support its growth. We also examined mammary adipose tissue from human breast cancer patients and found that Gatm is increased in the mammary adipose tissue of obese/overweight relative to normal weight breast cancer patients, supporting the translational relevance of our findings. Overall, we have established models of obesity-driven breast cancer, identified key gene candidates and pathways that affect obesity-dependent breast cancer, and have investigated underlying mechanisms.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Recommended Citation

Ackerman, Sarah, "The Role of Adipocytes in the Tumor Microenvironment in Obesity-Driven Breast Cancer Progression" (2020). Student Theses and Dissertations. 706.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/706