title: Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population.
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.
authors: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5942, USA. hkorkaya@med.umich.edu
authors: Hasan
authors: H
authors: Korkaya
authors: Gwang-Il
authors: GI
authors: Kim
authors: April
authors: A
authors: Davis
authors: Fayaz
authors: F
authors: Malik
authors: N Lynn
authors: NL
authors: Henry
authors: Suthinee
authors: S
authors: Ithimakin
authors: Ahmed A
authors: AA
authors: Quraishi
authors: Nader
authors: N
authors: Tawakkol
authors: Rosemarie
authors: R
authors: D'Angelo
authors: Amanda K
authors: AK
authors: Paulson
authors: Susan
authors: S
authors: Chung
authors: Tahra
authors: T
authors: Luther
authors: Hayley J
authors: HJ
authors: Paholak
authors: Suling
authors: S
authors: Liu
authors: Khaled A
authors: KA
authors: Hassan
authors: Qin
authors: Q
authors: Zen
authors: Shawn G
authors: SG
authors: Clouthier
authors: Max S
authors: MS
authors: Wicha
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018946:Chemokine CCL5; D015850:Interleukin-6; D016209:Interleukin-8; D051059:PTEN Phosphohydrolase; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C483024:CCL5 protein, human; C508606:CXCL8 protein, human; C508600:IL6 protein, human; C494929:PTEN protein, human