TARGETING MACROPHAGE MEDIATED SERM RESISTANCE IN BREAST CANCER.

GERMAN GIL, JASON NOWAK, JOHN KATZENELLENBOGEN, KENDALL NETTLES.

Simposio; Extrinsic Control of Tumor Genesis and Progression.; 2009

Despite the clinical benefit of endocrine therapies for breast cancer, a significant proportion of patients develop resistance. Tumour associated macrophages promote tumour growth, but it is not known if they play a role in endocrine resistance. Here we report that macrophages promote proliferation, migration, invasiveness, and tumour growth of breast cancer cells, and render estrogen-dependent breast cancer cells resistant to estrogen withdrawal or treatment with tamoxifen. Both the NF-κB and IL-6 signaling pathways are required for these responses, which include macrophage-mediated phosphorylation of the estrogen receptor (ER)-α, and activation of proliferative and proinflammatory genes in the breast cancer cells. Remarkably, an ERα antagonist that blocks NF-κB dependent inflammatory signaling abolishes the tumorigenic effects of macrophages by targeting these aberrant signaling programmes. Therefore, targeting both the ER and NF-κB pathways blocks macrophage-mediated endocrine resistance in breast cancer, offering this novel compound a great opportunities for use in prevention and treatment of refractory BREAST CANCER.