Macrophages-Tumor Microenvironment Induce Endocrine-Resistant Breast Cancer Proliferation via NFkB and growth factors

GERMAN GIL AND KENDALL W. NETTLES.

Congreso; SAIB; 2010

The tumour microenvironment plays vital roles in cancer but the molecular basis underlying these tumour-promoting effects is yet not fully understood. The NF-κB and growth factor signalling pathways are implicated in resistance to endocrine treatments in breast cancer. Here, we report that macrophage tumor associated induces proliferation of endocrine sensitive breast cancer cell lines in the absence of estradiol, or in the presence of tamoxifen. Macrophages-Breast Cancer Cells cocultured induced a sustained release of TNFα and IL-6 from both cell types, leading to activation of NF-κB, STAT3 and ERK in the breast cells. Furthermore this cells-crosstalk induces hyperphosphorylation of the estrogen receptor (ER) that rendered it constitutively active. The formation of a novel NF-κB/STAT3/phospho-ER complex at the Cyclin D1 gene induced proliferation regardless of ER ligand status, demonstrating that the tumor microenvironment can rapidly activate signalling pathways implicated in endocrine resistance.