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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

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 3

Deregulated MYC accelerates HER2 tumorigenesis in vivo.

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Deregulated MYC accelerates HER2 tumorigenesis in vivo.
(A) Schematic sh...
(A) Schematic showing the mouse strains crossed to generate the MYC;NeuNT (Rosa-LSL-Myv;LSL-NeuNT;Blg-Cre) mice. (B) Mammary gland tumor incidence from MYC (Rosa-LSL-Myc;Blg-Cre), NeuNT (LSL-NeuNT;Blg-Cre), and MYC;NeuNT (Rosa-LSL-Myc;LSL-NeuNT;Blg-Cre) mice. (C) Immunofluorescence images of p-S62-MYC in normal mammary gland from the MYC and MYC;NeuNT mice; and mammary tumors from MYC;NeuNT mice. Scale bars: 50 μm. (D) Mean fluorescence intensity (MFI) of p-Ser62-MYC was measured in p-Ser62-MYC–positive cells and compared between each mouse strain shown in C (n = 5 normal mammary gland/tumors per mouse strain). Asterisks denote significant differences in MFI: *P < 0.05, ****P < 0.0001, 1-way ANOVA corrected for multiple comparisons. (E) qRT-PCR of Myc mRNA levels in MYC (n = 4) and MYC;NeuNT (n = 6) normal mammary glands, as well as MYC;NeuNT mammary tumors (n = 6). Asterisks denote significant differences in expression: *P < 0.05 and **P < 0.01, Kruskal-Wallis test corrected for multiple comparisons. NS, not significant. (F) Images of representative (n = 45) chromogenic IHC for HER2 and ERα in MYC;NeuNT mammary tumors and adjacent normal mammary gland. Scale bars: 50 μm. (G) Representative H&E staining of macro and micro lung metastasis in MYC;NeuNT mice (n = 40). Scale bars: 200 μm. (H) GSEA results examining gene sets related to human ERBB2 breast tumors (left) and ERBB signaling (right), comparing MYC;NeuNT tumors with normal mammary gland. See Supplemental data set 2 for full GSEA results. NES, normalized enrichment score.
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