Shawn G Clouthier

Publications (37) View all

• Article: HER2 Drives Luminal Breast Cancer Stem Cells in the Absence of HER2 Amplification: Implications for Efficacy of Adjuvant Trastuzumab.

  Suthinee Ithimakin, Kathleen C Day, Fayaz Malik, Qin Zen, Scott J Dawsey, Tom F Bersano-Begey, Ahmed A Quraishi, Kathleen Woods Ignatoski, Stephanie Daignault, April Davis, [......], Nader Tawakkol, Tahra K Luther, Shawn G Clouthier, Whitney A Chadwick, Mark L Day, Celina G Kleer, Dafydd G Thomas, Daniel F Hayes, Hasan Korkaya, Max S Wicha
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  ABSTRACT: Although current breast cancer treatment guidelines limit the use of HER2-blocking agents to tumors with HER2 gene amplification, recent retrospective analyses suggest that a wider group of patients may benefit from this therapy. Using breast cancer cell lines, mouse xenograft models and matched human primary and metastatic tissues, we show that HER2 is selectively expressed in and regulates self-renewal of the cancer stem cell (CSC) population in estrogen receptor-positive (ER), HER2 luminal breast cancers. Although trastuzumab had no effects on the growth of established luminal breast cancer mouse xenografts, administration after tumor inoculation blocked subsequent tumor growth. HER2 expression is increased in luminal tumors grown in mouse bone xenografts, as well as in bone metastases from patients with breast cancer as compared with matched primary tumors. Furthermore, this increase in HER2 protein expression was not due to gene amplification but rather was mediated by receptor activator of NF-κB (RANK)-ligand in the bone microenvironment. These studies suggest that the clinical efficacy of adjuvant trastuzumab may relate to the ability of this agent to target the CSC population in a process that does not require HER2 gene amplification. Furthermore, these studies support a CSC model in which maximal clinical benefit is achieved when CSC targeting agents are administered in the adjuvant setting. Cancer Res; 73(5); 1635-46. ©2012 AACR.
  Cancer Research 03/2013; 73(5):1635-46. · 7.86 Impact Factor
• Article: Lin28 and HER2: two stem cell regulators conspire to drive aggressive breast cancer.

  Fayaz Malik, Hasan Korkaya, Shawn G Clouthier, Max S Wicha
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  ABSTRACT: Comment on: Feng C, et al. Cell Cycle 2012; 11:2486-94.
  Cell cycle (Georgetown, Tex.) 08/2012; 11(15):2780-1. · 5.36 Impact Factor
• Article: Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population.

  Hasan Korkaya, Gwang-Il Kim, April Davis, Fayaz Malik, N Lynn Henry, Suthinee Ithimakin, Ahmed A Quraishi, Nader Tawakkol, Rosemarie D'Angelo, Amanda K Paulson, Susan Chung, Tahra Luther, Hayley J Paholak, Suling Liu, Khaled A Hassan, Qin Zen, Shawn G Clouthier, Max S Wicha
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  ABSTRACT: Although inactivation of the PTEN gene has been implicated in the development of resistance to the HER2 targeting antibody trastuzumab, the mechanisms mediating this resistance remain elusive. We generated trastuzumab resistant cells by knocking down PTEN expression in HER2 overexpressing breast cancer cell lines and demonstrate that development of trastuzumab resistance in these cells is mediated by activation of an IL6 inflammatory feedback loop leading to expansion of the cancer stem cell (CSC) population. Long term trastuzumab treatment generates highly enriched CSCs which display an EMT phenotype secreting over 100-fold more IL6 than parental cells. An IL6 receptor antibody interrupted this inflammatory feedback loop reducing the cancer stem cell population resulting in decreased tumor growth and metastasis in mouse xenographs. These studies demonstrate that trastuzumab resistance may be mediated by an IL6 inflammatory loop and suggest that blocking this loop may provide alternative strategy to overcome trastuzumab resistance.
  Molecular cell 07/2012; 47(4):570-84. · 14.61 Impact Factor
• Source

  Available from: Shawn G Clouthier

  Article: MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells.

  Suling Liu, Shivani H Patel, Christophe Ginestier, Ingrid Ibarra, Rachel Martin-Trevino, Shoumin Bai, Sean P McDermott, Li Shang, Jia Ke, Sing J Ou, Amber Heath, Kevin J Zhang, Hasan Korkaya, Shawn G Clouthier, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Gregory J Hannon, Max S Wicha
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  ABSTRACT: MicroRNAs (miRNAs) play important roles in normal cellular differentiation and oncogenesis. microRNA93 (mir-93), a member of the mir106b-25 cluster, located in intron 13 of the MCM7 gene, although frequently overexpressed in human malignancies may also function as a tumor suppressor gene. Using a series of breast cancer cell lines representing different stages of differentiation and mouse xenograft models, we demonstrate that mir-93 modulates the fate of breast cancer stem cells (BCSCs) by regulating their proliferation and differentiation states. In "claudin(low)" SUM159 cells, expression of mir-93 induces Mesenchymal-Epithelial Transition (MET) associated with downregulation of TGFβ signaling and downregulates multiple stem cell regulatory genes, including JAK1, STAT3, AKT3, SOX4, EZH1, and HMGA2, resulting in cancer stem cell (CSC) depletion. Enforced expression of mir-93 completely blocks tumor development in mammary fat pads and development of metastases following intracardiac injection in mouse xenografts. The effect of mir-93 on the CSC population is dependent on the cellular differentiation state, with mir-93 expression increasing the CSC population in MCF7 cells that display a more differentiated "luminal" phenotype. mir-93 also regulates the proliferation and differentiation of normal breast stem cells isolated from reduction mammoplasties. These studies demonstrate that miRNAs can regulate the states and fates of normal and malignant mammary stem cells, findings which have important biological and clinical implications.
  PLoS Genetics 06/2012; 8(6):e1002751. · 8.69 Impact Factor
• Source

  Available from: Shawn G Clouthier

  Article: Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia.

  Sarah J Conley, Elizabeth Gheordunescu, Pramod Kakarala, Bryan Newman, Hasan Korkaya, Amber N Heath, Shawn G Clouthier, Max S Wicha
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  ABSTRACT: Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstrate that by generating intratumoral hypoxia in human breast cancer xenografts, the antiangiogenic agents sunitinib and bevacizumab increase the population of cancer stem cells. In vitro studies revealed that hypoxia-driven stem/progenitor cell enrichment is primarily mediated by hypoxia-inducible factor 1α. We further show that the Akt/β-catenin cancer stem cell regulatory pathway is activated in breast cancer cells under hypoxic conditions in vitro and in sunitinib-treated mouse xenografts. These studies demonstrate that hypoxia-driven cancer stem cell stimulation limits the effectiveness of antiangiogenic agents, and suggest that to improve patient outcome, these agents might have to be combined with cancer stem cell-targeting drugs.
  Proceedings of the National Academy of Sciences 02/2012; 109(8):2784-9. · 9.68 Impact Factor