title: Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation.
abstract: A major clinical problem in the treatment of breast cancer is mortality due to metastasis. Understanding the molecular mechanisms associated with metastasis should aid in designing new therapeutic approaches for breast cancer. Trastuzumab is the main therapeutic option for HER2+ breast cancer patients; however, the molecular basis for trastuzumab resistance (TZR) and subsequent metastasis is not known. Earlier, we found expression of basal-like molecular markers in TZR tissues from patients with invasive breast cancer.(( 1 )) The basal-like phenotype is a particularly aggressive form of breast cancer. This observation suggests that TZR might contribute to an aggressive phenotype. To understand if resistance to TZR can lead to basal-like phenotype, we generated a trastuzumab-resistant human breast cancer cell line (BT-474-R) that maintained human epidermal growth factor receptor 2 (HER2) overexpression and HER2 mediated signaling. Analysis showed that nuclear factor-kappa B (NF-κB) was constitutively activated in the BT-474-R cells, a feature similar to the basal-like tumor phenotype. Pharmacologic inhibition of NF-κB improved sensitivity of BT-474-R cells to trastuzumab. Interestingly, activation of HER2 independent NF-κB is not shown in luminal B breast cancer cells. Our study suggests that by activating the NF-κB pathway, luminal B cells may acquire a HER2+ basal-like phenotype in which NF-κB is constitutively activated; this notion is consistent with the recently proposed "progression through grade" or "evolution of resistance" hypothesis. Furthermore, we identified IKK-α/IKK-β and nuclear accumulation of RelA/p65 as the major determinants in the resistant cells. Thus our study additionally suggests that the nuclear accumulation of p65 may be a useful marker for identifying metastasis-initiating tumor cells and targeting RelA/p65 may limit metastasis of breast and other cancers associated with NF-κB activation.
authors.affiliation: 1 Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, California.|5 Current address: Department of Pharmacy, Okayama University Hospital , Okayama, Japan .
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kanzaki
authors.affiliation: 1 Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, California.|6 University of Illinois at Chicago , Department of Biochemistry and Molecular Genetics, Chicago, Illinois.
authors.forename: Nishit K
authors.initials: NK
authors.lastname: Mukhopadhya
authors.affiliation: 2 Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center , Los Angeles, California.|3 Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center , Los Angeles, California.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Cui
authors.affiliation: 2 Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center , Los Angeles, California.|4 Department of Surgery, Cedars-Sinai Medical Center , Los Angeles, California.
authors.forename: V Krishnan
authors.initials: VK
authors.lastname: Ramanujan
authors.affiliation: 1 Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, California.|2 Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center , Los Angeles, California.
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Murali
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D000068878:Trastuzumab / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D051550:I-kappa B Kinase; D016328:NF-kappa B; D009570:Nitriles; D018719:Erb-b2 Receptor Tyrosine Kinases; D013450:Sulfones; D051996:Transcription Factor RelA; D000068878:Trastuzumab; C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C498143:RELA protein, human; C508053:ERBB2 protein, human