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

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

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 9

Subtype-specific responses to therapy are overcome by MYC-targeted agents.

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Subtype-specific responses to therapy are overcome by MYC-targeted agent...
(A) Graph showing the change in tumor volume in MYC;NeuNT tumors over 30 days of treatment (Tx) with lapatinib or vehicle, using endpoint histological analysis to determine tumor molecular group (G1, G2, and G3; see Figure 2A). Asterisks denote significant differences in tumor volume (n shown on graph): *P < 0.05, 2-tailed Student’s t test. NS, not significant. (B) Representative immunofluorescence (IF) images of p-S62-MYC expression in MYC;NeuNT tumors after lapatinib or vehicle treatment (top) and IHC staining for Ki-67 in MYC;NeuNT tumors (bottom); n and quantification indicated in C. Scale bars: 50 μm. (C) Plots showing MFI for p-S62-MYC (top) and percentage Ki-67+ cells (bottom) in lapatinib-treated versus vehicle-treated MYC;NeuNT tumors, separating G3 tumors (green) from G1/G2 tumors (black) based on endpoint histology. Asterisks denote significant differences in cell MFI/Ki-67+ (n shown on plot): **P < 0.01, *P < 0.05, 1-way ANOVA corrected for multiple comparisons. (D) Graph showing MYC;NeuNT tumor volume over time following treatment with DT1154 (DT, 100 mg/kg b.i.d.) or vehicle for 30 days. Asterisks denote significant differences in tumor volume comparing DT1154-treated tumors to vehicle: ***P < 0.001, 2-tailed Student’s t test. (E) Representative immunofluorescence images of p-S62-MYC and Ki-67 in MYC;NeuNT tumors after DT1154 or vehicle treatment. Scale bars: 50 μm. (F) Plots showing MFI for p-S62-MYC (top) and percentage Ki-67+ cells (bottom) comparing DT1154- versus vehicle-treated MYC;NeuNT tumors, comparing groups as in C. Asterisks denote significant change in MFI/Ki-67+ (n shown on plot): **P < 0.01, ***P < 0.001, ****P < 0.0001, 1-way ANOVA corrected for multiple comparisons. (G) Representative IHC for p-ERK and p-AKT in MYC;NeuNT tumors after DT1154 or vehicle treatment, n = 6–7. Scale bars: 100 μm. (H) Plot showing the percentage of p-ERK– and p-AKT–positive cells in tumors following DT1154 and vehicle treatment. Tumor groups are marked by color as in C. Asterisks denote significant differences in positive cell frequency (n shown on plot): ***P < 0.001, 2-tailed Student’s t test.