HER2 Isoforms Uniquely Program Intratumor Heterogeneity and Predetermine Breast Cancer Trajectories During the Occult Tumorigenic Phase

  • Ginzel J
  • Acharya C
  • Lubkov V
  • et al.
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Abstract

◥ HER2-positive breast cancers are among the most heterogeneous breast cancer subtypes. The early amplification of HER2 and its known oncogenic isoforms provide a plausible mechanism in which distinct programs of tumor heterogeneity could be traced to the initial oncogenic event. Here a Cancer rainbow mouse simultaneously expressing fluorescently barcoded wildtype (WT HER2), exon-16 null (d16 HER2), and N-terminally truncated (p95 HER2) HER2 isoforms is used to trace tumorigenesis from initiation to invasion. Tumorigenesis was visualized using whole-gland fluorescent lineage tracing and single-cell molecular pathology. We demonstrate that within weeks of expression, morphologic aberrations were already present and unique to each HER2 isoform. Although WT HER2 cells were abundant throughout the mammary ducts, detectable lesions were exceptionally rare. In contrast, d16 HER2 and p95 HER2 induced rapid tumor development. d16 HER2 incited homogenous and proliferative luminal-like lesions which infrequently progressed to invasive phenotypes whereas p95 HER2 lesions were heterogenous and invasive at the smallest detectable stage. Distinct cancer trajectories were observed for d16 HER2 and p95 HER2 tumors as evidenced by oncogene-dependent changes in epithelial specification and the tumor microenvironment. These data provide direct experimental evidence that intratumor hetero-geneity programs begin very early and well in advance of screen or clinically detectable breast cancer. Implications: Although all HER2 breast cancers are treated equally, we show a mechanism by which clinically undetected HER2 isoforms program heterogenous cancer phenotypes through biased epithelial specification and adaptations within the tumor microenvironment. Wildtype HER2 Exon 16 splice isoform of HER2 N-terminally truncated HER2

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Ginzel, J. D., Acharya, C. R., Lubkov, V., Mori, H., Boone, P. G., Rochelle, L. K., … Snyder, J. C. (2021). HER2 Isoforms Uniquely Program Intratumor Heterogeneity and Predetermine Breast Cancer Trajectories During the Occult Tumorigenic Phase. Molecular Cancer Research, 19(10), 1699–1711. https://doi.org/10.1158/1541-7786.mcr-21-0215

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