RESUMEN
Metabolic reprogramming enables cancer cells to adapt to the changing microenvironment in order to maintain metabolic energy and to provide the necessary biological macromolecules required for cell growth and tumor progression. While changes in tumor metabolism have been long recognized as a hallmark of cancer, recent advances have begun to delineate the mechanisms that modulate metabolic pathways and the consequence of altered signaling on tumorigenesis. This is particularly evident in hormone receptor positive (HR+) breast cancers which account for approximately 70% of breast cancer cases. Emerging evidence indicates that HR+ breast tumors are dependent on multiple metabolic processes for tumor progression, metastasis, and therapeutic resistance and that changes in metabolic programs are driven, in part, by a number of key nuclear receptors including hormone-dependent signaling. In this review, we discuss the mechanisms and impact of hormone receptor mediated metabolic reprogramming on HR+ breast cancer genesis and progression as well as the therapeutic implications of these metabolic processes in this disease.
RESUMEN
Chromosome 11q13-14 amplification is a defining feature of high-risk hormone receptor-positive (HR+) breast cancer; however, the mechanism(s) by which this amplicon contributes to breast tumorigenesis remains unclear. In the current study, proteogenomic analyses of >3000 breast tumors from the TCGA, METABRIC and CPTAC studies demonstrated that carnitine palmitoyltransferase 1A (CPT1A), which is localized to this amplicon, is overexpressed at the mRNA and protein level in aggressive luminal tumors, strongly associated with indicators of tumor proliferation and a predictor of poor prognosis. In vitro genetic studies demonstrated that CPT1A is required for and can promote luminal breast cancer proliferation, survival, as well as colony and mammosphere formation. Since CPT1A is the rate-limiting enzyme during fatty acid oxidation (FAO), our data indicate that FAO may be essential for these tumors. Pharmacologic inhibition of FAO prevented in vitro and in vivo tumor growth and cell proliferation as well as promoted apoptosis in luminal breast cancer cells and orthotopic xenograft tumor models. Collectively, our data establish an oncogenic role for CPT1A and FAO in HR+ luminal tumors and provide preclinical evidence and rationale supporting further investigation of FAO as a potential therapeutic opportunity for the treatment of HR+ breast cancer.