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TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer
Neil E. Bhola, … , Rebecca S. Cook, Carlos L. Arteaga
Neil E. Bhola, … , Rebecca S. Cook, Carlos L. Arteaga
Published February 8, 2013
Citation Information: J Clin Invest. 2013;123(3):1348-1358. https://doi.org/10.1172/JCI65416.
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Research Article Oncology Article has an altmetric score of 41

TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer

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Abstract

After an initial response to chemotherapy, many patients with triple-negative breast cancer (TNBC) have recurrence of drug-resistant metastatic disease. Studies with TNBC cells suggest that chemotherapy-resistant populations of cancer stem-like cells (CSCs) with self-renewing and tumor-initiating capacities are responsible for these relapses. TGF-β has been shown to increase stem-like properties in human breast cancer cells. We analyzed RNA expression in matched pairs of primary breast cancer biopsies before and after chemotherapy. Biopsies after chemotherapy displayed increased RNA transcripts of genes associated with CSCs and TGF-β signaling. In TNBC cell lines and mouse xenografts, the chemotherapeutic drug paclitaxel increased autocrine TGF-β signaling and IL-8 expression and enriched for CSCs, as indicated by mammosphere formation and CSC markers. The TGF-β type I receptor kinase inhibitor LY2157299, a neutralizing TGF-β type II receptor antibody, and SMAD4 siRNA all blocked paclitaxel-induced IL8 transcription and CSC expansion. Moreover, treatment of TNBC xenografts with LY2157299 prevented reestablishment of tumors after paclitaxel treatment. These data suggest that chemotherapy-induced TGF-β signaling enhances tumor recurrence through IL-8–dependent expansion of CSCs and that TGF-β pathway inhibitors prevent the development of drug-resistant CSCs. These findings support testing a combination of TGF-β inhibitors and anticancer chemotherapy in patients with TNBC.

Authors

Neil E. Bhola, Justin M. Balko, Teresa C. Dugger, María Gabriela Kuba, Violeta Sánchez, Melinda Sanders, Jamie Stanford, Rebecca S. Cook, Carlos L. Arteaga

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Figure 4

Paclitaxel and TGF-β induce SMAD4-dependent expression of IL-8.

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Paclitaxel and TGF-β induce SMAD4-dependent expression of IL-8.
(A) SUM1...
(A) SUM159 and BT549 cells were treated with 5 to 10 nM paclitaxel for 4 days. RT-qPCR analysis was performed to assess IL8 and GAPDH RNA levels (*P < 0.05, **P < 0.003). (B) SUM159 cells were treated with 2.5 ng/ml TGF-β with or without 5 μM LY2157299 and grown as mammospheres. Media was collected, and IL-8 protein levels were measured by ELISA; IL-8 levels were normalized to total protein (*P = 0.02). (C) SUM159 cells were transfected with control or SMAD4 siRNA and plated as mammospheres with or without TGF-β1. After 6 days, mammospheres and media were collected and analyzed for IL-8 levels by ELISA. IL-8 levels were normalized to total protein (*P < 0.001). (D) SUM159 cells were transfected with control or both CXCR1 and CXCR2 siRNA and plated as mammospheres with or without 2.5 ng/ml TGF-β1 for 6 days. Mammosphere number was then quantitated, as described in Methods (*P = 0.016). (E) SUM159 cells were transfected with control or SMAD4 siRNA. Forty-eight hours later, 10 nM paclitaxel was added for 24 hours before mRNA extraction and RT-qPCR using IL-8–specific primers (*P < 0.002, **P = 0.002). (F) RT-qPCR analysis of IL8 mRNA levels in SUM159 and BT549 cells treated with 5 μM LY2157299 and 5 nM paclitaxel (BT549 cells) or 10 nM paclitaxel (SUM159 cells) as indicated for 6 days (*P < 0.007, **P < 0.001). (G) Media from cells treated with paclitaxel with or without LY2157299 was collected and subjected to IL-8 ELISA assay. Raw IL-8 levels were normalized to cell number (*P < 0.001). Error bars indicate SEM.

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