HER2 Isoforms Uniquely Program Intratumor Heterogeneity and Predetermine Breast Cancer Trajectories During the Occult Tumorigenic Phase
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 (WTHER2), exon-16 null (d16HER2), and N-terminally truncated (p95HER2) 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 WTHER2 cells were abundant throughout the mammary ducts, detectable lesions were exceptionally rare. In contrast, d16HER2 and p95HER2 induced rapid tumor development. d16HER2 incited homogenous and proliferative luminal-like lesions which infrequently progressed to invasive phenotypes whereas p95HER2 lesions were heterogenous and invasive at the smallest detectable stage. Distinct cancer trajectories were observed for d16HER2 and p95HER2 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 15, 2021
- Source ID
- 10.1158/1541-7786.mcr-21-0215
Entities
People
- Alexander D. Borowsky
- Chaitanya Acharya
- Erika J Crosby
- Herbert Kim Lyerly
- Hidetoshi Mori
- Jane Q. Chen
- Jeffrey I. Everitt
- Joshua D Ginzel
- Joshua Snyder
- Lauren K. Rochelle
- Lawrence S Barak
- Marc G. Caron
- Neil E. Hubbard
- Peter G. Boone
- Robert Cardiff
- Veronica Lubkov
- Wendy L. Roberts
- Zachary C Hartman
Organizations
- Duke University
- Duke University Hospital
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- National Cancer Institute
- United States Department of Defense
- University of California, Davis