%0 Journal Article
%T Tumor-Associated Macrophages Induce Endocrine Therapy Resistance in ER+ Breast Cancer Cells
%A Andr¨¦s M. Castellaro
%A Cecilia E. Di Tada
%A Germ¨¢n A. Gil
%A Mar¨ªa C. Rodriguez-Baili
%J Archive of "Cancers".
%D 2019
%R 10.3390/cancers11020189
%X Antiestrogenic adjuvant treatments are first-line therapies in patients with breast cancer positive for estrogen receptor (ER+). Improvement of their treatment strategies is needed because most patients eventually acquire endocrine resistance and many others are initially refractory to anti-estrogen treatments. The tumor microenvironment plays essential roles in cancer development and progress; however, the molecular mechanisms underlying such effects remain poorly understood. Breast cancer cell lines co-cultured with TNF-¦Á-conditioned macrophages were used as pro-inflammatory tumor microenvironment models. Proliferation, migration, and colony formation assays were performed to evaluate tamoxifen and ICI 182,780 resistance and confirmed in a mouse-xenograft model. Molecular mechanisms were investigated using cytokine antibody arrays, WB, ELISA, ChIP, siRNA, and qPCR-assays. In our simulated pro-inflammatory tumor microenvironment, tumor-associated macrophages promoted proliferation, migration, invasiveness, and breast tumor growth of ER+ cells, rendering these estrogen-dependent breast cancer cells resistant to estrogen withdrawal and tamoxifen or ICI 182,780 treatment. Crosstalk between breast cancer cells and conditioned macrophages induced sustained release of pro-inflammatory cytokines from both cell types, activation of NF-¦ÊB/STAT3/ERK in the cancer cells and hyperphosphorylation of ER¦Á, which resulted constitutively active. Our simulated tumor microenvironment strongly altered endocrine and inflammatory signaling pathways in breast cancer cells, leading to endocrine resistance in these cells
%K macrophages
%K tumor microenvironment
%K breast cancer
%K estrogen receptor
%K tamoxifen
%K endocrine resistance
%K TNF-¦Á
%K IL-6
%K NF-¦ÊB
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406935/