Cell Lineage Tracing Links ERα Loss in Erbb2-Positive Breast Cancers to the Arising of a Highly Aggressive Breast Cancer Subtype

Authors

Yunfeng Ding
Yonghong Liu
Dong-Kee Lee
Zhangwei Tong
Xiaobin Yu
Yi Li
Yong Xu
Rainer B Lanz
Bert W O'Malley
Jianming Xu

Publication Date

5-25-2021

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2100673118

PMID

34006643

PMCID

PMC8166171

PubMedCentral® Posted Date

5-18-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Breast Neoplasms, Carcinoma, Intraductal, Noninfiltrating, Cell Line, Tumor, Cell Lineage, Cell Proliferation, Cell Transformation, Neoplastic, Estrogen Receptor alpha, Female, GATA3 Transcription Factor, Gene Expression Regulation, Neoplastic, Hepatocyte Nuclear Factor 3-alpha, Humans, Lung Neoplasms, Mice, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Neoplasm Invasiveness, Promoter Regions, Genetic, Receptor, ErbB-2, Signal Transduction, Tumor Burden, Xenograft Model Antitumor Assays, cell lineage tracing, estrogen receptor, HER2+ breast cancer, cancer cell origin, metastasis

Abstract

HER2-positive (HER2+) breast cancers (BrCs) contain approximately equal numbers of ERα+HER2+ and ERα−HER2+ cases. An enduring obstacle is the unclear cell lineage-related characteristics of these BrCs. Although ERα+HER2+ BrCs could lose ERα to become ERα−HER2+ BrCs, direct evidence is missing. To investigate ERα dependencies and their implications during BrC growth and metastasis, we generated ERαCreRFP-T mice that produce an RFP-marked ERα+ mammary gland epithelial cell (MGEC) lineage. RCAS virus-mediated expression of Erbb2, a rodent Her2 homolog, first produced comparable numbers of ERα+RFP+Erbb2+ and ERα−RFP−Erbb2+ MGECs. Early hyperplasia developed mostly from ERα+RFP+Erbb2+ cells and ERα−RFP−Erbb2+ cells in these lesions were rare. The subsequently developed ductal carcinomas in situ had 64% slow-proliferating ERα+RFP+Erbb2+ cells, 15% fast-proliferating ERα−RFP+Erbb2+ cells derived from ERα+RFP+Erbb2+ cells, and 20% fast-proliferating ERα−RFP−Erbb2+ cells. The advanced tumors had mostly ERα−RFP+Erbb2+ and ERα−RFP−Erbb2+ cells and only a very small population of ERα+RFP+Erbb2+ cells. In ERα−RFP+Erbb2+ cells, GATA3 and FoxA1 decreased expression and ERα promoter regions became methylated, consistent with the loss of ERα expression. Lung metastases consisted of mostly ERα−RFP+Erbb2+ cells, a few ERα−RFP−Erbb2+ cells, and no ERα+RFP+Erbb2+ cells. The high metastatic capacity of ERα−RFP+Erbb2+ cells was associated with ERK1/2 activation. These results show that the slow-proliferating, nonmetastatic ERα+RFP+Erbb2+ cells progressively lose ERα during tumorigenesis to become fast-proliferating, highly metastatic ERα−RFP+Erbb2+ cells. The ERα−Erbb2+ BrCs with an ERα+ origin are more aggressive than those ERα−Erbb2+ BrCs with an ERα− origin, and thus, they should be distinguished and treated differently in the future.