title: Upregulation of ER Signaling as an Adaptive Mechanism of Cell Survival in HER2-Positive Breast Tumors Treated with Anti-HER2 Therapy.
abstract: OBJECTIVE
  To investigate the direct effect and therapeutic consequences of epidermal growth factor receptor 2 (HER2)-targeting therapy on expression of estrogen receptor (ER) and Bcl2 in preclinical models and clinical tumor samples.
  
  
  METHODS
  Archived xenograft tumors from two preclinical models (UACC812 and MCF7/HER2-18) treated with ER and HER2-targeting therapies and also HER2+ clinical breast cancer specimens collected in a lapatinib neoadjuvant trial (baseline and week 2 posttreatment) were used. Expression levels of ER and Bcl2 were evaluated by immunohistochemistry and Western blot analysis. The effects of Bcl2 and ER inhibition, by ABT-737 and fulvestrant, respectively, were tested in parental versus lapatinib-resistant UACC812 cells in vitro.
  
  
  RESULTS
  Expression of ER and Bcl2 was significantly increased in xenograft tumors with acquired resistance to anti-HER2 therapy compared with untreated tumors in both preclinical models (UACC812: ER P = 0.0014; Bcl2 P < 0.001 and MCF7/HER2-18: ER P = 0.0007; Bcl2 P = 0.0306). In the neoadjuvant clinical study, lapatinib treatment for 2 weeks was associated with parallel upregulation of ER and Bcl2 (Spearman coefficient: 0.70; P = 0.0002). Importantly, 18% of tumors originally ER-negative (ER(-)) converted to ER(+) upon anti-HER2 therapy. In ER(-)/HER2(+) MCF7/HER2-18 xenografts, ER reexpression was primarily observed in tumors responding to potent combination of anti-HER2 drugs. Estrogen deprivation added to this anti-HER2 regimen significantly delayed tumor progression (P = 0.018). In the UACC812 cells, fulvestrant, but not ABT-737, was able to completely inhibit anti-HER2-resistant growth (P < 0.0001).
  
  
  CONCLUSIONS
  HER2 inhibition can enhance or restore ER expression with parallel Bcl2 upregulation, representing an ER-dependent survival mechanism potentially leading to anti-HER2 resistance.
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Giuliano
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Huizhong
authors.initials: H
authors.lastname: Hu
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Yen-Chao
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Fu
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Agostina
authors.initials: A
authors.lastname: Nardone
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Herrera
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Sufeng
authors.initials: S
authors.lastname: Mao
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Contreras
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gutierrez
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Carmine
authors.initials: C
authors.lastname: De Angelis
authors.affiliation: Department of Biomedical Engineering, OHSU Center for Spatial Systems Biomedicine, OHSU Knight Cancer Institute, Portland, Oregon.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, OHSU Center for Spatial Systems Biomedicine, OHSU Knight Cancer Institute, Portland, Oregon.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Heiser
authors.affiliation: Department of Biomedical Engineering, OHSU Center for Spatial Systems Biomedicine, OHSU Knight Cancer Institute, Portland, Oregon.
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.affiliation: Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Lopez-Tarruella
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Pavlick
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Texas.
authors.forename: Meghana V
authors.initials: MV
authors.lastname: Trivedi
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Chamness
authors.affiliation: Methodist Cancer Center, Houston Methodist Hospital, Houston, Texas.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Mothaffar F
authors.initials: MF
authors.lastname: Rimawi
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. rschiff@bcm.edu.
authors.forename: Rachel
authors.initials: R
authors.lastname: Schiff
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D002470:Cell Survival; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D058990:Molecular Targeted Therapy; D020360:Neoadjuvant Therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D015415:Biomarkers; D000077341:Lapatinib; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone