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

Authors: DING, YUNFENG - Baylor College Of Medicine; LIU, YONGHONG - Baylor College Of Medicine; LEE, DONG-KEE - Baylor College Of Medicine; TONG, ZHANGWEI - Baylor College Of Medicine; YU, XIAOBIN - Baylor College Of Medicine; LI, YI - Baylor College Of Medicine; XU, YONG - Children'S Nutrition Research Center (CNRC); LANZ, RAINER - Baylor College Of Medicine; O'MALLEY, BERT - Baylor College Of Medicine; XU, JIANMING - Baylor College Of Medicine

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/20/2021
Publication Date: 5/25/2021
Citation: Ding, Y., Liu, Y., Lee, D., Tong, Z., Yu, X., Li, Y., Xu, Y., Lanz, R., O'Malley, B., Xu, J. 2021. Cell lineage tracing links ERa loss in Erbb2-positive breast cancers to the arising of a highly aggressive breast cancer subtype. Proceedings of the National Academy of Sciences (PNAS). 118:21. https://doi.org/10.1073/pnas.2100673118.
DOI: https://doi.org/10.1073/pnas.2100673118

Interpretive Summary: Breast cancers are often categorized by which receptors are present in the cancerous cells, such as the HER2 and ERalpha receptors. Of the cancers that are HER2-positive (HER2+), some are ERalpha-positive (ERa+) and some are ERa-negative (ERa-), but it was previously unclear whether cancerous cells could originate as ERa+ and then become ERa- as the tumor progresses. In this study, a mice model of breast cancer showed that it is possible for a HER2+ERa+ cancer to lose its ERa receptor. Interestingly, the cells that lost ERa became fast-proliferating and highly metastatic. These results show that ERa- cancers that used to be ERa+ are more aggressive than those that originated as ERa-, and suggests that these two cancers should be distinguished and treated differently.

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