Breast tumors of the basal-like, hormone receptor-negative, subtype remain an unmet clinical challenge, as patients exhibit a high rate of recurrence and poor survival. Co-evolution of the malignant mammary epithelium and its underlying stroma instigates cancer-associated fibroblasts (CAFs) to endorse most, if not all, hallmarks of cancer progression. Here, we delineate a previously unappreciated role for CAFs as determinants of the molecular subtype of breast cancer. We identified a paracrine cross-talk between cancer cells expressing platelet-derived growth factor (PDGF)-CC and CAFs expressing the cognate receptors in human basal-like mammary carcinomas. Genetic or pharmacological intervention with PDGF-CC activity in mouse models of cancer resulted in conversion of basal-like breast cancers into a hormone receptor-positive state that conferred sensitivity to endocrine therapy in previously impervious tumors. We conclude that specification of the basal-like subtype of breast cancer is under microenvironmental control and therapeutically actionable in order to achieve sensitivity to endocrine therapy.

Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited β-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells.

The androgen receptor (AR) is the key oncogenic driver of prostate cancer and despite implementation of novel AR targeting therapies, patient outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen regulated cellular processes, in order to more effectively target the AR-dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, however the relationship between AR and the lipidome remain undefined. Using mass spectrometrybased lipidomics, this study revealed increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgenregulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL Fatty Acid Elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts and clinical tumors. Assessment of mRNA and protein in large-scale datasets revealed ELOVL5 as the predominant ELOVL expressed in both primary and metastatic prostate cancer, and upregulated compared to non-malignant prostate. ELOVL5 depletion by siRNA markedly altered mitochondrial function to induce oxidative stress, resulting in significant inhibition of prostate cancer cell viability, 3D growth, and in vivo tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell viability caused by ELOVL5 knockdown. We have identified lipid elongation as a pro-survival metabolic pathway in prostate cancer that is androgenregulated, critical for metastasis and targetable via ELOVL5.