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.

中文翻译：

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在HER2 ⁺乳腺癌模型中解除MYC的调控可模拟人的肿瘤间异质性

c-MYC（MYC）癌蛋白通常在人类乳腺癌中过表达；然而，其在驱动疾病表型中的作用了解甚少。在这里，我们调查MYC在HER2 ⁺疾病中的作用，并检查HER2表达与HER2 ^+中MYC磷酸化之间的关系。肿瘤和表征在扩增的HER2乳腺癌小鼠NeuNT模型中调节MYC表达的功能作用。单独失调的MYC不会致癌，但与NeuNT的共表达会导致MYC Ser62磷酸化增加并加速肿瘤发生。与单独的NeuNT相比，产生的肿瘤具有转移性，并与存活率降低相关。MYC； NeuNT肿瘤具有增加的肿瘤间异质性，包括在NeuNT肿瘤中未观察到的肿瘤亚型，其表现出明显的化生组织学和较差的存活率。MYC； NeuNT肿瘤的不同亚型通过分子表达与扩增的HER2（雌激素受体阴性）人类肿瘤相匹配，鉴定此鼠模型的临床前效用，以研究扩增的HER2乳腺癌中亚型特异性的差异。我们显示这些亚型对临床以HER2 / EGFR为靶点的疗法具有不同的敏感性，但是PP2A的小分子激活剂（调节MYC Ser62磷酸化的磷酸酶）规避了这些亚型特异性差异并普遍抑制了肿瘤的生长，证明了该疗法的实用性。这种针对放宽MYC乳腺癌的方法。