TGF-β Inhibition Enhances Chemotherapy Action Against Triple-Negative Breast Cancer

J Clin Invest. 2013 Mar;123(3):1348-58. doi: 10.1172/JCI65416. Epub 2013 Feb 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • Mice
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Paclitaxel / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyrazoles / pharmacology*
  • Quinolines / pharmacology*
  • RNA, Small Interfering / genetics
  • Receptor, ErbB-2 / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Signal Transduction
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism
  • Spheroids, Cellular / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta / physiology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Phytogenic
  • CXCL8 protein, human
  • Interleukin-8
  • Pyrazoles
  • Quinolines
  • RNA, Small Interfering
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Receptors, Transforming Growth Factor beta
  • SMAD4 protein, human
  • Smad4 Protein
  • Transforming Growth Factor beta
  • LY-2157299
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • Paclitaxel