title: Trastuzumab resistance induces EMT to transform HER2(+) PTEN(-) to a triple negative breast cancer that requires unique treatment options.
abstract: Although trastuzumab is an effective treatment in early stage HER2(+) breast cancer the majority of advanced HER2(+) breast cancers develop trastuzumab resistance, especially in the 40% of breast cancers with loss of PTEN. However, HER2(+) breast cancer patients continue to receive trastuzumab regardless PTEN status and the consequence of therapy in these patients is unknown. We demonstrate that continued use of trastuzumab in HER2(+) cells with loss of PTEN induces the epithelial-mesenchymal transition (EMT) and transform HER2(+) to a triple negative breast cancer. These transformed cells exhibited mesenchymal morphology and gene expression markers, while parent HER2(+) cells showed epithelial morphology and markers. The transformed cells exhibited loss of dependence on ERBB family signaling (such as HER2, HER3, HER4, BTC, HRG, EGF) and reduced estrogen and progesterone receptors. Continued use of trastuzumab in HER2(+) PTEN(-) cells increased the frequency of cancer stem cells (CSCs) and metastasis potential. Strikingly, parental HER2(+) cells and transformed resistant cells respond to treatment differently. Transformed resistant cells were sensitive to chemical probe (sulforaphane) through inhibition of IL-6/STAT3/NF-κB positive feedback loop whereas parental HER2(+) cells did not respond. This data suggests that trastuzumab resistance in HER2(+) PTEN- breast cancer induces EMT and subtype switching, which requires unique treatment options.
authors.affiliation: Department of Pharmaceutical Sciences, The University of Michigan, 428 Church St., Ann Arbor, MI 48109-1065.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Burnett
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgia Regents University Cancer Center, 1410 Laney Walker Boulevard CN2136 Augusta, GA 30912.
authors.forename: Hasan
authors.initials: H
authors.lastname: Korkaya
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgia Regents University Cancer Center, 1410 Laney Walker Boulevard CN2136 Augusta, GA 30912.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Ouzounova
authors.affiliation: Department of Biostatistics, The University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109-2029.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5942.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Conley
authors.affiliation: Department of Pharmaceutical Sciences, The University of Michigan, 428 Church St., Ann Arbor, MI 48109-1065.
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Newman
authors.affiliation: Department of Pharmaceutical Sciences, The University of Michigan, 428 Church St., Ann Arbor, MI 48109-1065.
authors.forename: Lichao
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutical Sciences, The University of Michigan, 428 Church St., Ann Arbor, MI 48109-1065.
authors.forename: Jamie N
authors.initials: JN
authors.lastname: Connarn
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, 50 W 12th Ave, Columbus, OH 43210.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Research Center of Basic Medical Science &Cancer Institute and Hospital, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin 300070, People's Republic of China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5942.
authors.forename: Max S
authors.initials: MS
authors.lastname: Wicha
authors.affiliation: Department of Pharmaceutical Sciences, The University of Michigan, 428 Church St., Ann Arbor, MI 48109-1065.
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000068878:Trastuzumab / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D050796:STAT3 Transcription Factor; D000068878:Trastuzumab; C494086:STAT3 protein, human; C494929:PTEN protein, human