Cell lineage tracing links ERα loss in Erbb2-positive breast cancers to the arising of a highly aggressive breast cancer subtype

Author:

Ding YunfengORCID,Liu YonghongORCID,Lee Dong-KeeORCID,Tong Zhangwei,Yu XiaobinORCID,Li YiORCID,Xu Yong,Lanz Rainer B.ORCID,O’Malley Bert W.ORCID,Xu JianmingORCID

Abstract

HER2-positive (HER2+) breast cancers (BrCs) contain approximately equal numbers of ERα+HER2+ and ERαHER2+ cases. An enduring obstacle is the unclear cell lineage-related characteristics of these BrCs. Although ERα+HER2+ BrCs could lose ERα to become ERαHER2+ 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 ERαRFPErbb2+ MGECs. Early hyperplasia developed mostly from ERα+RFP+Erbb2+ cells and ERαRFPErbb2+ cells in these lesions were rare. The subsequently developed ductal carcinomas in situ had 64% slow-proliferating ERα+RFP+Erbb2+ cells, 15% fast-proliferating ERαRFP+Erbb2+ cells derived from ERα+RFP+Erbb2+ cells, and 20% fast-proliferating ERαRFPErbb2+ cells. The advanced tumors had mostly ERαRFP+Erbb2+ and ERαRFPErbb2+ cells and only a very small population of ERα+RFP+Erbb2+ cells. In ERαRFP+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 ERαRFP+Erbb2+ cells, a few ERαRFPErbb2+ cells, and no ERα+RFP+Erbb2+ cells. The high metastatic capacity of ERαRFP+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 ERαRFP+Erbb2+ cells. The ERαErbb2+ BrCs with an ERα+ origin are more aggressive than those ERαErbb2+ BrCs with an ERα origin, and thus, they should be distinguished and treated differently in the future.

Funder

International Cancer Imaging Society

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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