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Article

Tumor-Associated Macrophages Induce Endocrine Therapy Resistance in ER+ Breast Cancer Cells

1
Departamento de Química Biológica, Facultad de Ciencias Químicas, CIQUIBIC CONICET, Universidad Nacional de Córdoba, Ciudad Universitaria, Córdoba X5000HUA, Argentina
2
Laboratorio de Inmunohistoquímica, Fundación para el Progreso de la Medicina, Córdoba X5000EMS, Argentina
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(2), 189; https://doi.org/10.3390/cancers11020189
Received: 8 December 2018 / Revised: 9 January 2019 / Accepted: 15 January 2019 / Published: 6 February 2019
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-α-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-κB/STAT3/ERK in the cancer cells and hyperphosphorylation of ERα, 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. View Full-Text
Keywords: macrophages; tumor microenvironment; breast cancer; estrogen receptor; tamoxifen; endocrine resistance; TNF-α; IL-6; NF-κB macrophages; tumor microenvironment; breast cancer; estrogen receptor; tamoxifen; endocrine resistance; TNF-α; IL-6; NF-κB
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MDPI and ACS Style

Castellaro, A.M.; Rodriguez-Baili, M.C.; Di Tada, C.E.; Gil, G.A. Tumor-Associated Macrophages Induce Endocrine Therapy Resistance in ER+ Breast Cancer Cells. Cancers 2019, 11, 189. https://doi.org/10.3390/cancers11020189

AMA Style

Castellaro AM, Rodriguez-Baili MC, Di Tada CE, Gil GA. Tumor-Associated Macrophages Induce Endocrine Therapy Resistance in ER+ Breast Cancer Cells. Cancers. 2019; 11(2):189. https://doi.org/10.3390/cancers11020189

Chicago/Turabian Style

Castellaro, Andrés M., María C. Rodriguez-Baili, Cecilia E. Di Tada, and Germán A. Gil 2019. "Tumor-Associated Macrophages Induce Endocrine Therapy Resistance in ER+ Breast Cancer Cells" Cancers 11, no. 2: 189. https://doi.org/10.3390/cancers11020189

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