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HER2 Isoforms Uniquely Program Intratumor Heterogeneity and Predetermine Breast Cancer Trajectories During the Occult Tumorigenic Phase
- Source :
- Mol Cancer Res, Molecular cancer research : MCR, vol 19, iss 10
- Publication Year :
- 2021
-
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. 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.
- Subjects :
- Gene isoform
Cancer Research
Carcinogenesis
Receptor, ErbB-2
Knockout
Oncology and Carcinogenesis
Breast Neoplasms
Biology
medicine.disease_cause
Article
Mice
Breast cancer
ErbB-2
Breast Cancer
medicine
Tumor Microenvironment
2.1 Biological and endogenous factors
Animals
Protein Isoforms
Oncology & Carcinogenesis
Aetiology
skin and connective tissue diseases
Molecular Biology
neoplasms
Cancer
Mice, Knockout
Tumor microenvironment
Neoplastic
Molecular pathology
Wild type
medicine.disease
Phenotype
Gene Expression Regulation, Neoplastic
Good Health and Well Being
Oncology
Gene Expression Regulation
Cancer research
Female
Receptor
Developmental Biology
Subjects
Details
- ISSN :
- 15573125
- Volume :
- 19
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Molecular cancer research : MCR
- Accession number :
- edsair.doi.dedup.....3c799658e9caec1d1e76a3e04ecd77ab