Deregulating MYC in a model of HER2+ breast cancer mimics human intertumoral heterogeneity

Tyler Risom, Xiaoyan Wang, Juan Liang, Xiaoli Zhang, Carl Pelz, Lydia G. Campbell, Jenny Eng, Koei Chin, Caroline Farrington, Goutham Narla, Ellen M. Langer, Xiao Xin Sun, Yulong Su, Colin J. Daniel, Mu Shui Dai, Christiane V. Löhr, Rosalie C. Sears

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

The c-MYC (MYC) oncoprotein is often overexpressed in human breast cancer; however, its role in driving disease phenotypes is poorly understood. Here, we investigate the role of MYC in HER2+ disease, examining the relationship between HER2 expression and MYC phosphorylation in HER2+ patient tumors and characterizing the functional effects of deregulating MYC expression in the murine NeuNT model of amplified-HER2 breast cancer. Deregulated MYC alone was not tumorigenic, but coexpression with NeuNT resulted in increased MYC Ser62 phosphorylation and accelerated tumorigenesis. The resulting tumors were metastatic and associated with decreased survival compared with NeuNT alone. MYC;NeuNT tumors had increased intertumoral heterogeneity including a subtype of tumors not observed in NeuNT tumors, which showed distinct metaplastic histology and worse survival. The distinct subtypes of MYC;NeuNT tumors match existing subtypes of amplified- HER2, estrogen receptor-negative human tumors by molecular expression, identifying the preclinical utility of this murine model to interrogate subtype-specific differences in amplified-HER2 breast cancer. We show that these subtypes have differential sensitivity to clinical HER2/EGFR-targeted therapeutics, but small-molecule activators of PP2A, the phosphatase that regulates MYC Ser62 phosphorylation, circumvents these subtype-specific differences and ubiquitously suppresses tumor growth, demonstrating the therapeutic utility of this approach in targeting deregulated MYC breast cancers.

Original languageEnglish (US)
Pages (from-to)231-246
Number of pages16
JournalJournal of Clinical Investigation
Volume130
Issue number1
DOIs
StatePublished - Jan 2 2020

ASJC Scopus subject areas

  • Medicine(all)

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    Risom, T., Wang, X., Liang, J., Zhang, X., Pelz, C., Campbell, L. G., Eng, J., Chin, K., Farrington, C., Narla, G., Langer, E. M., Sun, X. X., Su, Y., Daniel, C. J., Dai, M. S., Löhr, C. V., & Sears, R. C. (2020). Deregulating MYC in a model of HER2+ breast cancer mimics human intertumoral heterogeneity. Journal of Clinical Investigation, 130(1), 231-246. https://doi.org/10.1172/JCI126390