TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer
Neil E. Bhola,Justin M. Balko,Teresa C. Dugger,Maria G. Kuba,Violeta Sanchez,Melinda E. Sanders,Jamie C. Stanford,Rebecca S. Cook,Carlos L. Arteaga +8 more
Reads0
Chats0
TLDR
Analysis of RNA expression in matched pairs of primary breast cancer biopsies before and after chemotherapy suggests that chemotherapy-induced TGF-β signaling enhances tumor recurrence through IL-8-dependent expansion of CSCs and that T GF-β pathway inhibitors prevent the development of drug-resistant C SCs.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.read more
Citations
More filters
Journal ArticleDOI
Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease
TL;DR: The most relevant molecular findings in TNBC from the past decade are discussed and the most promising therapeutic opportunities derived from these data are discussed.
Journal ArticleDOI
Combination cancer immunotherapy and new immunomodulatory targets.
TL;DR: The leading drug targets that are expressed on tumour cells and in the tumour microenvironment that allow enhancement of the antitumour immune response are discussed.
Journal ArticleDOI
Tackling the cancer stem cells — what challenges do they pose?
TL;DR: The signalling pathways that create cancer stem cells, cell-intrinsic mechanisms that could be exploited for selective elimination or induction of their differentiation, and the role of the tumour microenvironment in sustaining them are discussed.
Journal ArticleDOI
Targeting TGF-β Signaling in Cancer.
TL;DR: The rationale for targeting TGF-β signaling in cancer is reviewed, the clinical status of pharmacological inhibitors are summarized, and the direct effects of TGF -β signaling blockade on tumor and stromal cells are discussed.
Journal ArticleDOI
Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment.
TL;DR: This work seeks to review the most recent efforts to classify TNBC based on the comprehensive profiling of tumors for cellular composition and molecular features to help improve risk stratification of patients, guide treatment decisions and surveillance, and help identify new targets for drug development.
References
More filters
Journal ArticleDOI
Prospective identification of tumorigenic breast cancer cells
Muhammad Al-Hajj,Max S. Wicha,Adalberto Benito-Hernandez,Sean J. Morrison,Sean J. Morrison,Michael F. Clarke +5 more
TL;DR: The ability to prospectively identify tumorigenic cancer cells will facilitate the elucidation of pathways that regulate their growth and survival and strategies designed to target this population may lead to more effective therapies.
Journal ArticleDOI
The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells
Sendurai A. Mani,Wenjun Guo,Mai Jing Liao,Elinor Ng Eaton,Ayyakkannu Ayyanan,Alicia Y. Zhou,Mary W. Brooks,Ferenc Reinhard,Cheng Cheng Zhang,Michail Shipitsin,Lauren L. Campbell,Kornelia Polyak,Cathrin Brisken,Jing Yang,Robert A. Weinberg +14 more
TL;DR: It is reported that the induction of an EMT in immortalized human mammary epithelial cells (HMLEs) results in the acquisition of mesenchymal traits and in the expression of stem-cell markers, and it is shown that those cells have an increased ability to form mammospheres, a property associated with mammARY epithelial stem cells.
Journal ArticleDOI
Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence
Rebecca Dent,Maureen E. Trudeau,Kathleen I. Pritchard,Wedad Hanna,Harriet K. Kahn,Carol Sawka,Lavina Lickley,Ellen Rawlinson,Ping Sun,Steven A. Narod +9 more
TL;DR: Triple-negative breast cancers have a more aggressive clinical course than other forms of breast cancer, but the adverse effect is transient.
Journal ArticleDOI
ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome.
Christophe Ginestier,Min Hee Hur,Emmanuelle Charafe-Jauffret,Florence Monville,Julie Dutcher,Marty Brown,Jocelyne Jacquemier,Patrice Viens,Celina G. Kleer,Suling Liu,Anne F. Schott,Daniel F. Hayes,Daniel Birnbaum,Max S. Wicha,Gabriela Dontu +14 more
TL;DR: It is shown that normal and cancer human mammary epithelial cells with increased aldehyde dehydrogenase activity (ALDH) have stem/progenitor properties and these cells contain the subpopulation of normal breast epithelium with the broadest lineage differentiation potential and greatest growth capacity in a xenotransplant model.
Journal ArticleDOI
Cancer stem cells in solid tumours: accumulating evidence and unresolved questions
TL;DR: The cancer stem cell (CSC) hypothesis provides an attractive cellular mechanism to account for the therapeutic refractoriness and dormant behaviour exhibited by many of these tumours.