Upregulation of mucin4 in ER-positive/HER2-overexpressing breast cancer xenografts with acquired resistance to endocrine and HER2-targeted therapies

Albert C. Chen, Ilenia Migliaccio, Mothaffar Rimawi, Sara Lopez-Tarruella, Chad J. Creighton, Suleiman Massarweh, Catherine Huang, Yen Chao Wang, Surinder K. Batra, M. Carolina Gutierrez, C. Kent Osborne, Rachel Schiff

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

We studied resistance to endocrine and HER2-targeted therapies using a xenograft model of estrogen receptor positive (ER)/HER2-overexpressing breast cancer. Here, we report a novel phenotype of drug resistance in this model. MCF7/HER2-18 xenografts were treated with endocrine therapy alone or in combination with lapatinib and trastuzumab (LT) to inhibit HER2. Archival tumor tissues were stained with hematoxylin and eosin and with mucicarmine. RNA extracted from tumors at early time points and late after acquired resistance were analyzed for mucin4 (MUC4) expression by microarray and quantitative reverse transcriptase-PCR. Protein expression of the MUC4, ER, and HER2 signaling pathways was measured by immunohistochemistry and western blotting. The combination of the potent anti-HER2 regimen LT with either tamoxifen (Tam ? LT) or estrogen deprivation (ED ? LT) can cause complete eradication of ER-positive/HER2-overexpressing tumors in mice. Tumors developing resistance to this combination, as well as those acquiring resistance to endocrine therapy alone, exhibited a distinct histological and molecular phenotype-a striking increase in mucin-filled vacuoles and upregulation of several mucins including MUC4. At the onset of resistance, MUC4 mRNA and protein were increased. These tumors also showed upregulation and reactivation of HER2 signaling, while losing ER protein and the estrogenregulated gene progesterone receptor. Mucins are upregulated in a preclinical model of ER-positive/HER2-overexpressing breast cancer as resistance develops to the combination of endocrine and anti-HER2 therapy. These mucin-rich tumors reactivate the HER2 pathway and shift their molecular phenotype to become more ER-negative/HER2-positive.

Original languageEnglish (US)
Pages (from-to)583-593
Number of pages11
JournalBreast Cancer Research and Treatment
Volume134
Issue number2
DOIs
StatePublished - Jul 2012

Keywords

  • Breast cancer
  • Drug resistance
  • Endocrine therapy
  • HER2 therapy
  • Mucin4
  • Mucinated phenotype
  • Mucins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Chen, A. C., Migliaccio, I., Rimawi, M., Lopez-Tarruella, S., Creighton, C. J., Massarweh, S., Huang, C., Wang, Y. C., Batra, S. K., Gutierrez, M. C., Kent Osborne, C., & Schiff, R. (2012). Upregulation of mucin4 in ER-positive/HER2-overexpressing breast cancer xenografts with acquired resistance to endocrine and HER2-targeted therapies. Breast Cancer Research and Treatment, 134(2), 583-593. https://doi.org/10.1007/s10549-012-2082-9