Lysine metabolism is a novel metabolic tumor suppressor pathway in breast cancer

The International Agency for Research on Cancer determined that obesity is the primary preventable cause of breast cancer. The nuclear receptor peroxisome proliferator activated receptor & gamma; (PPAR & gamma;) binds inflammatory mediators in obesity and its expression is reduced in human breast cancer. We created a new model to better understand how the obese microenvironment alters nuclear receptor function in breast cancer. The obesity related cancer phenotype was PPAR & gamma; dependent; deletion of PPAR & gamma; in mammary epithelium which is a tumor suppressor in lean mice unexpectedly increased tumor latency, reduced the luminal progenitor (LP) tumor cell fraction, and increased autophagic and senescent cells. Loss of PPAR & gamma; expression in mammary epithelium of obese mice increased expression of 2-aminoadipate semialdehyde synthase (AASS) which regulates lysine catabolism to acetoacetate. PPAR & gamma;-associated co-repressors and activators regulated AASS expression via a canonical response element. AASS expression was significantly reduced in human breast cancer, and AASS overexpression or acetoacetate treatment inhibited proliferation and induced autophagy and senescence in human breast cancer cell lines. Genetic or pharmacologic HDAC inhibition promoted autophagy and senescence in mammary tumor cells in vitro and in vivo. We concluded that lysine metabolism is a novel metabolic tumor suppressor pathway in breast cancer.

Automated summary

Obesity is the primary preventable cause of breast cancer, and the expression of the nuclear receptor PPAR & gamma; is altered in obese mice, leading to an increased risk of breast cancer. The increased expression of PPAR & gamma; in mammary epithelium of obese mice is associated with higher expression of solute carrier proteins, which contributes to the development of breast cancer.