HSD11β1 promotes EMT-mediated breast cancer metastasis

Abnormal biosyntheses of steroid hormones and dysregulation of steroid hormone receptors contribute to breast cancer metastasis but the mechanisms of that are poorly understand. Here we report a stress hormone producing enzyme, Hydroxysteroid (11-Beta) Dehydrogenase 1 (HSD11β1) promotes breast cancer metastasis. HSD11β1 was ectopically expressed in seventy-one percent of triple-negative breast tumors and correlated with shorter overall survival. HSD11β1 significantly promoted breast cancer metastasis through induction of epithelial-to-mesenchymal transition (EMT); conversely, pharmacologic and genetic inhibition of HSD11β1 suppressed metastatic progression of breast cancer cells. Moreover, 11-hydroxyprogesterone (11-OHP) whom HSD11β1 produced in breast cancer cells, conferred metastatic properties on non-metastatic breast cancer cells through induction of EMT. We identified Peroxisome Proliferator-activated Receptor Alpha (PPAR-α) as essential for both HSD11β1 and 11OHP-driven EMT. Knockdown of PPAR-α induced MET on HSD11β1-expressing breast cancer cells. Taken together, HSD11β1 promotes breast cancer metastasis and would be a novel target for suppressing breast cancer metastasis.