title: Breast Cancer Anti-Estrogen Resistance 4 (BCAR4) Drives Proliferation of IPH-926 lobular Carcinoma Cells.
abstract: BACKGROUND
  Most breast cancers depend on estrogenic growth stimulation. Functional genetic screenings in in vitro cell models have identified genes, which override growth suppression induced by anti-estrogenic drugs like tamoxifen. Using that approach, we have previously identified Breast Cancer Anti-Estrogen Resistance 4 (BCAR4) as a mediator of cell proliferation and tamoxifen-resistance. Here, we show high level of expression and function of BCAR4 in human breast cancer.
  
  
  METHODS
  BCAR4 mRNA expression was evaluated by (q)RT-PCR in a panel of human normal tissues, primary breast cancers and cell lines. A new antibody raised against C78-I97 of the putative BCAR4 protein and used for western blot and immunoprecipitation assays. Furthermore, siRNA-mediated gene silencing was implemented to study the function of BCAR4 and its downstream targets ERBB2/3.
  
  
  RESULTS
  Except for placenta, all human normal tissues tested were BCAR4-negative. In primary breast cancers, BCAR4 expression was comparatively rare (10%), but associated with enhanced proliferation. Relative high BCAR4 mRNA expression was identified in IPH-926, a cell line derived from an endocrine-resistant lobular breast cancer. Moderate BCAR4 expression was evident in MDA-MB-134 and MDA-MB-453 breast cancer cells. BCAR4 protein was detected in breast cancer cells with ectopic (ZR-75-1-BCAR4) and endogenous (IPH-926, MDA-MB-453) BCAR4 mRNA expression. Knockdown of BCAR4 inhibited cell proliferation. A similar effect was observed upon knockdown of ERBB2/3 and exposure to lapatinib, implying that BCAR4 acts in an ERBB2/3-dependent manner.
  
  
  CONCLUSIONS
  BCAR4 encodes a functional protein, which drives proliferation of endocrine-resistant breast cancer cells. Lapatinib, a clinically approved EGFR/ERBB2 inhibitor, counteracts BCAR4-driven tumor cell growth, a clinical relevant observation.
authors: Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors: Ton
authors: T
authors: van Agthoven
authors: Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors: Lambert C J
authors: LC
authors: Dorssers
authors: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors: Ulrich
authors: U
authors: Lehmann
authors: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors: Hans
authors: H
authors: Kreipe
authors: Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors: Leendert H J
authors: LH
authors: Looijenga
authors: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors: Matthias
authors: M
authors: Christgen
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism
chemical_list: D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D062085:RNA, Long Noncoding; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C553206:BCAR4 non-coding RNA, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human