Breast and Prostate Cancer Lipid Metabolism and Metabolic Interactions with Adipocytes

Abstract

Obesity is defined as excessive accumulation of adipose tissue and is associated with many chronic diseases, such as cardiovascular disease and type 2 diabetes. Obesity is also associated with reduced survival and increased recurrence of breast and prostate cancers (BrCa & PrCa). Breast tissue is composed primarily of metabolically active adipocytes that produce fatty acids (FAs), and normal mammary epithelial cells which can use adipocyte-derived FAs for biosynthesis and energy production. A similar relationship is emerging between local adipocytes in the peri-prostatic bed and PrCa cells. The amount of lipid contained in mammary and peri-prostatic adipocytes is increased in obesity and furthermore increased peri-prostatic adiposity correlates with aggressive PrCa. There is emerging evidence for cross-talk between BrCa and PrCa cells and local mature adipocytes. In addition, aberrant lipid metabolism is a common feature of both BrCa and PrCa cells. However, little attention has been paid to the role adipocyte-derived FAs may play as metabolic substrates for cancer cell progression. The overall aim of this project was to define the metabolic interactions between adipocytes and cancer cells, to examine the role of obesity in BrCa and PrCa by focusing on the role of extracellular and adipocyte-derived FAs and cancer cell metabolism in cancer cell progression. BrCa cells mobilised stored FAs from adipocytes that promotes their growth. To investigate the effect of obesity on BrCa progression an in vitro model of ‘obese’ adipocytes was developed. The rate of transfer of FAs from ‘obese’ adipocytes to BrCa cells was greater compared to ‘lean’. Enhanced proliferation and migration rates and altered FA, glucose and glutamine metabolism was observed in both MCF-7 and MDA-MB-231 cells when co-cultured with ‘obese’ adipocytes. Adipocyte ATGL and HSL are required for adipocyte-mediated effects on proliferation of aggressive MDA-MB-231 (ER-) cells but not in less aggressive ER+ MCF-7 (ER+) cells. In addition, findings presented in this thesis demonstrated that MCF-7 and MDA-MB-231 cells were sensitive to lipid availability in the microenvironment and the extracellular FAs were able to alter intracellular FA metabolism. In addition, elevated lipid levels protected MDA-MB-231 cells from cellular stresses including palmitate and serum-starvation. Similar studies were performed using PrCa cells, which too increased adipocyte lipolysis. The rate of transfer of FAs from ‘obese’ adipocytes to PrCa cells was greater compared to ‘lean’. Increased proliferation and altered FA, glucose and glutamine metabolism was observed in PC-3 cells when co-cultured with ‘lean’ and ‘obese’ adipocytes. Moreover, extracellular and intracellular FA metabolism was altered in PC-3 and C4-2B cells when exposed to higher levels of extracellular FAs and this was correlated with increased survival under serum-starvation and palmitate toxicity in PC-3 cells. Overall, the studies reported in this thesis demonstrate that FAs, both extracellularly present in the media and adipocyte-derived, are drivers of altered metabolism in BrCa and PrCa cells. These metabolic changes promote BrCa and PrCa cell growth as well as survival under stress conditions.