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Deregulating MYC in a model of HER2+ breast cancer mimics human intertumoral heterogeneity
Tyler Risom, … , Christiane V. Löhr, Rosalie C. Sears
Tyler Risom, … , Christiane V. Löhr, Rosalie C. Sears
Published November 25, 2019
Citation Information: J Clin Invest. 2020;130(1):231-246. https://doi.org/10.1172/JCI126390.
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Research Article Cell biology Oncology Article has an altmetric score of 4

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

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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.

Authors

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

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Figure 1

HER2 regulates MYC protein stability and phosphorylation at Ser62.

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HER2 regulates MYC protein stability and phosphorylation at Ser62.
(A) W...
(A) Western and quantitative RT-PCR (qRT-PCR) analysis in MCF10A-Ctrl and MCF10A-Neu8142 cells showing endogenous MYC protein (representative Western blots [n = 3], left) and mRNA levels (right graph, mean ± SEM, n = 3). (B) Western blot and MYC half-life calculation in MCF10A-Ctrl (top) and MCF10A-Neu8142 cells (bottom) infected with Ad-MYC. Representative Westerns and mean half-life ± SD indicated, from 2 independent experiments. CHX, cycloheximide. (C) Western blot of MCF10A-TR-MYC-Ctrl and MCF10A-TR-MYC-Neu8142 cells treated with doxycycline for 24 hours. Representative (n = 3) expression of ectopic MYC protein levels and p-S62-MYC levels are shown and quantified. (D) Immunofluorescence images of 2 human HER2+ breast tumors and patient-matched normal region adjacent to tumor 1. Scale bars: 50 μm. See Supplemental Figure 1D for quantification of these and additional tumors and normal tissues.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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