气候变化领域集成服务门户(CCPortal): Cell lineage tracing links ERα loss in Erbb2-positive breast cancers to the arising of a highly aggressive breast cancer subtype

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DOI	10.1073/pnas.2100673118
	Cell lineage tracing links ERα loss in Erbb2-positive breast cancers to the arising of a highly aggressive breast cancer subtype
	Ding Y.; Liu Y.; Lee D.-K.; Tong Z.; Yu X.; Li Y.; Xu Y.; Lanz R.B.; O’Malley B.W.; Xu J.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:21
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	cancer cell origin; Cell lineage tracing; estrogen receptor; HER2+ breast cancer; metastasis
语种	英语
scopus关键词	epidermal growth factor receptor 2; estrogen receptor alpha; hepatocyte nuclear factor 3alpha; progesterone receptor; transcription factor GATA 3; uvomorulin; epidermal growth factor receptor 2; ERBB2 protein, human; ESR1 protein, human; estrogen receptor alpha; FOXA1 protein, human; GATA3 protein, human; hepatocyte nuclear factor 3alpha; MAPK1 protein, human; MAPK3 protein, human; mitogen activated protein kinase 1; mitogen activated protein kinase 3; transcription factor GATA 3; animal cell; animal experiment; animal model; animal tissue; Article; breast cancer; breast epithelium; cancer cell; cancer grading; cancer growth; cell lineage; cell proliferation; cell survival; immunohistochemistry; in vivo study; intraductal carcinoma; long terminal repeat; lung metastasis; male; metastasis potential; nonhuman; promoter region; protein depletion; protein expression; protein function; tumor growth; tumor volume; animal; breast tumor; cell lineage; cell transformation; drug screening; female; gene expression regulation; genetics; human; immunology; lung tumor; metabolism; mouse; pathology; signal transduction; tumor cell line; tumor invasion; 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
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251175
作者单位	Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, United States; Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, United States
推荐引用方式 GB/T 7714	Ding Y.,Liu Y.,Lee D.-K.,et al. Cell lineage tracing links ERα loss in Erbb2-positive breast cancers to the arising of a highly aggressive breast cancer subtype[J],2021,118(21).
APA	Ding Y..,Liu Y..,Lee D.-K..,Tong Z..,Yu X..,...&Xu J..(2021).Cell lineage tracing links ERα loss in Erbb2-positive breast cancers to the arising of a highly aggressive breast cancer subtype.Proceedings of the National Academy of Sciences of the United States of America,118(21).
MLA	Ding Y.,et al."Cell lineage tracing links ERα loss in Erbb2-positive breast cancers to the arising of a highly aggressive breast cancer subtype".Proceedings of the National Academy of Sciences of the United States of America 118.21(2021).