title: ErbB3 downregulation enhances luminal breast tumor response to antiestrogens.
abstract: Aberrant regulation of the erythroblastosis oncogene B (ErbB) family of receptor tyrosine kinases (RTKs) and their ligands is common in human cancers. ErbB3 is required in luminal mammary epithelial cells (MECs) for growth and survival. Since breast cancer phenotypes may reflect biological traits of the MECs from which they originate, we tested the hypothesis that ErbB3 drives luminal breast cancer growth. We found higher ERBB3 expression and more frequent ERBB3 gene copy gains in luminal A/B breast cancers compared with other breast cancer subtypes. In cell culture, ErbB3 increased growth of luminal breast cancer cells. Targeted depletion of ErbB3 with an anti-ErbB3 antibody decreased 3D colony growth, increased apoptosis, and decreased tumor growth in vivo. Treatment of clinical breast tumors with the antiendocrine drug fulvestrant resulted in increased ErbB3 expression and PI3K/mTOR signaling. Depletion of ErbB3 in fulvestrant-treated tumor cells reduced PI3K/mTOR signaling, thus decreasing tumor cell survival and tumor growth. Fulvestrant treatment increased phosphorylation of all ErbB family RTKs; however, phospho-RTK upregulation was not seen in tumors treated with both fulvestrant and anti-ErbB3. These data indicate that upregulation of ErbB3 in luminal breast cancer cells promotes growth, survival, and resistance to fulvestrant, thus suggesting ErbB3 as a target for breast cancer treatment.
authors.forename: Meghan M
authors.initials: MM
authors.lastname: Morrison
authors.forename: Katherine
authors.initials: K
authors.lastname: Hutchinson
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Williams
authors.forename: Jamie C
authors.initials: JC
authors.lastname: Stanford
authors.forename: Justin M
authors.initials: JM
authors.lastname: Balko
authors.forename: Christian
authors.initials: C
authors.lastname: Young
authors.forename: Maria G
authors.initials: MG
authors.lastname: Kuba
authors.forename: Violeta
authors.initials: V
authors.lastname: Sánchez
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Williams
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Hicks
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.forename: Suleiman
authors.initials: S
authors.lastname: Massarweh
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Cook
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D049109:Cell Proliferation; D002470:Cell Survival; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D018628:Gene Dosage; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D018931:Antineoplastic Agents, Hormonal; D066246:ErbB Receptors; D004958:Estradiol; D020847:Estrogen Receptor Modulators; D000077267:Fulvestrant; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human