27-Hydroxycholesterol Promotes Cell-Autonomous, ER-Positive Breast Cancer Growth

• 27HC stimulates ER+ breast tumor growth in mice
• 27HC is increased in human ER+ breast tumors
• Tumor CYP7B1 expression is negatively associated with prognosis
• 27HC causes cell-autonomous, ER-dependent, and RET-dependent proliferation

SummaryTo date, estrogen is the only known endogenous estrogen receptor (ER) ligand that promotes ER+ breast tumor growth. We report that the cholesterol metabolite 27-hydroxycholesterol (27HC) stimulates MCF-7 cell xenograft growth in mice. More importantly, in ER+ breast cancer patients, 27HC content in normal breast tissue is increased compared to that in cancer-free controls, and tumor 27HC content is further elevated. Increased tumor 27HC is correlated with diminished expression of CYP7B1, the 27HC metabolizing enzyme, and reduced expression of CYP7B1 in tumors is associated with poorer patient survival. Moreover, 27HC is produced by MCF-7 cells, and it stimulates cell-autonomous, ER-dependent, and GDNF-RET-dependent cell proliferation. Thus, 27HC is a locally modulated, nonaromatized ER ligand that promotes ER+ breast tumor growth.

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