title: NF-κB activation-induced anti-apoptosis renders HER2-positive cells drug resistant and accelerates tumor growth.
abstract: Breast cancers with HER2 overexpression are sensitive to drugs targeting the receptor or its kinase activity. HER2-targeting drugs are initially effective against HER2-positive breast cancer, but resistance inevitably occurs. We previously found that NF-κB is hyperactivated in a subset of HER2-positive breast cancer cells and tissue specimens. In this study, we report that constitutively active NF-κB rendered HER2-positive cancer cells resistant to anti-HER2 drugs and cells selected for lapatinib resistance upregulated NF-κB. In both circumstances, cells were antiapoptotic and grew rapidly as xenografts. Lapatinib-resistant cells were refractory to HER2 and NF-κB inhibitors alone but were sensitive to their combination, suggesting a novel therapeutic strategy. A subset of NF-κB-responsive genes was overexpressed in HER2-positive and triple-negative breast cancers, and patients with this NF-κB signature had poor clinical outcome. Anti-HER2 drug resistance may be a consequence of NF-κB activation, and selection for resistance results in NF-κB activation, suggesting that this transcription factor is central to oncogenesis and drug resistance. Clinically, the combined targeting of HER2 and NF-κB suggests a potential treatment paradigm for patients who relapse after anti-HER2 therapy. Patients with these cancers may be treated by simultaneously suppressing HER2 signaling and NF-κB activation.
  
  
  CONCLUSIONS
  The combination of an inhibitor of IκB kinase (IKK) inhibitor and anti-HER2 drugs may be a novel treatment strategy for drug-resistant human breast cancers.
authors: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02115.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors: Shannon T
authors: ST
authors: Bailey
authors: Department of Cancer Biology, Dana-Farber Cancer Institute & Harvard Medical School. Boston, MA 02115.
authors: Penelope L
authors: PL
authors: Miron
authors: Department of Cancer Biology, Dana-Farber Cancer Institute & Harvard Medical School. Boston, MA 02115.
authors: Yoon J
authors: YJ
authors: Choi
authors: Department of Cancer Biology, Dana-Farber Cancer Institute & Harvard Medical School. Boston, MA 02115.
authors: Bose
authors: B
authors: Kochupurakkal
authors: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02115.
authors: Gautam
authors: G
authors: Maulik
authors: Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors: Scott J
authors: SJ
authors: Rodig
authors: Department of Cancer Biology, Dana-Farber Cancer Institute & Harvard Medical School. Boston, MA 02115.
authors: Ruiyang
authors: R
authors: Tian
authors: Department of Cancer Biology, Dana-Farber Cancer Institute & Harvard Medical School. Boston, MA 02115.
authors: Kathleen M
authors: KM
authors: Foley
authors: Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors: Teresa
authors: T
authors: Bowman
authors: Department of Cancer Biology, Dana-Farber Cancer Institute & Harvard Medical School. Boston, MA 02115.
authors: Alexander
authors: A
authors: Miron
authors: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02115.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors: Myles
authors: M
authors: Brown
authors: Department of Cancer Biology, Dana-Farber Cancer Institute & Harvard Medical School. Boston, MA 02115.|Department of Surgery, Brigham & Women's Hospital and Harvard Medical School. Boston, MA 02115.
authors: J Dirk
authors: JD
authors: Iglehart
authors: Department of Cancer Biology, Dana-Farber Cancer Institute & Harvard Medical School. Boston, MA 02115.|Department of Surgery, Brigham & Women's Hospital and Harvard Medical School. Boston, MA 02115.
authors: K Biswas
authors: KB
authors: Debajit
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000077341:Lapatinib; D016328:NF-kappa B; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human