title: TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer.
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: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, USA.
authors: Neil E
authors: NE
authors: Bhola
authors: Justin M
authors: JM
authors: Balko
authors: Teresa C
authors: TC
authors: Dugger
authors: María Gabriela
authors: MG
authors: Kuba
authors: Violeta
authors: V
authors: Sánchez
authors: Melinda
authors: M
authors: Sanders
authors: Jamie
authors: J
authors: Stanford
authors: Rebecca S
authors: RS
authors: Cook
authors: Carlos L
authors: CL
authors: Arteaga
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016209:Interleukin-8; D017239:Paclitaxel; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011804:Quinolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D018125:Receptors, Transforming Growth Factor beta; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; C508606:CXCL8 protein, human; C497796:SMAD4 protein, human; C557799:LY-2157299; C508053:ERBB2 protein, human
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