ly-2157299 and Breast-Neoplasms

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.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Gene Expression; Gene Knockdown Techniques; Humans; Interleukin-8; Mice; Mice, Nude; Neoplastic Stem Cells; Paclitaxel; Protein Serine-Threonine Kinases; Pyrazoles; Quinolines; Receptor, ErbB-2; Receptor, Transforming Growth Factor-beta Type I; Receptors, Estrogen; Receptors, Progesterone; Receptors, Transforming Growth Factor beta; RNA, Small Interfering; Signal Transduction; Smad4 Protein; Spheroids, Cellular; Transforming Growth Factor beta; Xenograft Model Antitumor Assays