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

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 (d1)6HER2 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 heterogeneity programs begin very early and well in advance of screen or clinically detectable breast cancer.

Automated summary

The study demonstrates that HER2-positive breast cancers display high heterogeneity, with distinct tumor trajectories observed for (d16)HER2 and (p95)HER2. The findings suggest that intratumor heterogeneity programs start early, well before breast cancer is screenable or clinically detectable.