ErbB3 downregulation enhances luminal breast tumor response to antiestrogens.

Morrison MM, Hutchinson K, Williams MM, Stanford JC, Balko JM, Young C, Kuba MG, Sánchez V, Williams AJ, Hicks DJ, Arteaga CL, Prat A, Perou CM, Earp HS, Massarweh S, Cook RS
J Clin Invest. 2013 123 (10): 4329-43

PMID: 23999432 · PMCID: PMC3784526 · DOI:10.1172/JCI66764

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.

MeSH Terms (29)

Animals Antibodies, Monoclonal Antineoplastic Agents, Hormonal Breast Neoplasms Cell Proliferation Cell Survival Down-Regulation Drug Resistance, Neoplasm Drug Synergism ErbB Receptors Estradiol Estrogen Receptor Modulators Female Fulvestrant Gene Dosage Gene Expression Gene Expression Regulation, Neoplastic Humans MCF-7 Cells Mice Mice, Inbred BALB C Mice, Nude Oligonucleotide Array Sequence Analysis Receptor, ErbB-2 Receptor, ErbB-3 Signal Transduction Survival Analysis Transcriptome Xenograft Model Antitumor Assays

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