ErbB3 downregulation enhances luminal breast tumor response to antiestrogens

Meghan M. Morrison, Katherine Hutchinson, Michelle M. Williams, Jamie C. Stanford, Justin M. Balko, Christian Young, Maria G. Kuba, Violeta Sánchez, Andrew J. Williams, Donna J. Hicks, Carlos L. Arteaga, Aleix Prat, Charles M. Perou, H. Shelton Earp, Suleiman Massarweh, Rebecca S. Cook

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)4329-4343
Number of pages15
JournalJournal of Clinical Investigation
Volume123
Issue number10
DOIs
StatePublished - Oct 1 2013

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Estrogen Receptor Modulators
Down-Regulation
Breast Neoplasms
Growth
Receptor Protein-Tyrosine Kinases
Neoplasms
Phosphatidylinositol 3-Kinases
Oncogenes
Cell Survival
Breast
Up-Regulation
Epithelial Cells
Anti-Idiotypic Antibodies
Cell Culture Techniques
Phosphorylation
fulvestrant
Apoptosis
Ligands
Phenotype
Survival

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Morrison, M. M., Hutchinson, K., Williams, M. M., Stanford, J. C., Balko, J. M., Young, C., ... Cook, R. S. (2013). ErbB3 downregulation enhances luminal breast tumor response to antiestrogens. Journal of Clinical Investigation, 123(10), 4329-4343. https://doi.org/10.1172/JCI66764

ErbB3 downregulation enhances luminal breast tumor response to antiestrogens. / Morrison, Meghan M.; Hutchinson, Katherine; Williams, Michelle M.; Stanford, Jamie C.; Balko, Justin M.; Young, Christian; Kuba, Maria G.; Sánchez, Violeta; Williams, Andrew J.; Hicks, Donna J.; Arteaga, Carlos L.; Prat, Aleix; Perou, Charles M.; Shelton Earp, H.; Massarweh, Suleiman; Cook, Rebecca S.

In: Journal of Clinical Investigation, Vol. 123, No. 10, 01.10.2013, p. 4329-4343.

Research output: Contribution to journalArticle

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, Shelton Earp, H, Massarweh, S & Cook, RS 2013, 'ErbB3 downregulation enhances luminal breast tumor response to antiestrogens', Journal of Clinical Investigation, vol. 123, no. 10, pp. 4329-4343. https://doi.org/10.1172/JCI66764
Morrison MM, Hutchinson K, Williams MM, Stanford JC, Balko JM, Young C et al. ErbB3 downregulation enhances luminal breast tumor response to antiestrogens. Journal of Clinical Investigation. 2013 Oct 1;123(10):4329-4343. https://doi.org/10.1172/JCI66764
Morrison, Meghan M. ; Hutchinson, Katherine ; Williams, Michelle M. ; Stanford, Jamie C. ; Balko, Justin M. ; Young, Christian ; Kuba, Maria G. ; Sánchez, Violeta ; Williams, Andrew J. ; Hicks, Donna J. ; Arteaga, Carlos L. ; Prat, Aleix ; Perou, Charles M. ; Shelton Earp, H. ; Massarweh, Suleiman ; Cook, Rebecca S. / ErbB3 downregulation enhances luminal breast tumor response to antiestrogens. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 10. pp. 4329-4343.
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