Fatty acid synthase regulates estrogen receptor-α signaling in breast cancer cells

Fatty acid synthase (FASN), the key enzyme for endogenous synthesis of fatty acids, is overexpressed and hyperactivated in a biologically aggressive subset of sex steroid-related tumors, including breast carcinomas. Using pharmacological and genetic approaches, we assessed the molecular relationship between FASN signaling and estrogen receptor alpha (ERa) signaling in breast cancer. The small compound C75, a synthetic slow-binding inhibitor of FASN activity, induced a dramatic augmentation of estradiol (E-2)-stimulated, ER alpha-driven transcription. FASN and ER alpha were both necessary for the synergistic activation of ER alpha transcriptional activity that occurred following co-exposure to C75 and E-2: first, knockdown of FASN expression using RNAi (RNA interference) drastically lowered (> 100 fold) the amount of E-2 required for optimal activation of ER alpha-mediated transcriptional activity; second, FASN blockade synergistically increased E-2-stimulated ER alpha-mediated transcriptional activity in ER alpha-negative breast cancer cells stably transfected with ER alpha, but not in ER alpha-negative parental cells. Non-genomic, E2-regulated cross-talk between the ER alpha and MAPK pathways participated in these phenomena. Thus, treatment with the pure antiestrogen ICI 182 780 or the potent and specific inhibitor of MEK/ERK, U0126, was sufficient to abolish the synergistic nature of the interaction between FASN blockade and E2-stimulated ER alpha transactivation. FASN inhibition suppressed E2-stimulated breast cancer cell proliferation and anchorage-independent colony formation while promoting the reduction of ER alpha protein. FASN blockade resulted in the increased expression and nuclear accumulation of the cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(Kip1), two critical mediators of the therapeutic effects of antiestrogen in breast cancer, while inactivating AKT, a key mediator of E-2-promoted anchorage-independent growth. The ability of FASN to regulate E-2/ER alpha signaling may represent a promising strategy for anticancer treatment involving a new generation of FASN inhibitors.