| First Author | Ding Y | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 21 | PubMed ID | 34006643 |
| Mgi Jnum | J:306304 | Mgi Id | MGI:6713250 |
| Doi | 10.1073/pnas.2100673118 | Citation | Ding Y, et al. (2021) Cell lineage tracing links ERalpha loss in Erbb2-positive breast cancers to the arising of a highly aggressive breast cancer subtype. Proc Natl Acad Sci U S A 118(21):e2100673118 |
| abstractText | HER2-positive (HER2(+)) breast cancers (BrCs) contain approximately equal numbers of ERalpha(+)HER2(+) and ERalpha(-)HER2(+) cases. An enduring obstacle is the unclear cell lineage-related characteristics of these BrCs. Although ERalpha(+)HER2(+) BrCs could lose ERalpha to become ERalpha(-)HER2(+) BrCs, direct evidence is missing. To investigate ERalpha dependencies and their implications during BrC growth and metastasis, we generated ERalpha(Cre)RFP-T mice that produce an RFP-marked ERalpha(+) mammary gland epithelial cell (MGEC) lineage. RCAS virus-mediated expression of Erbb2, a rodent Her2 homolog, first produced comparable numbers of ERalpha(+)RFP(+)Erbb2(+) and ERalpha(-)RFP(-)Erbb2(+) MGECs. Early hyperplasia developed mostly from ERalpha(+)RFP(+)Erbb2(+) cells and ERalpha(-)RFP(-)Erbb2(+) cells in these lesions were rare. The subsequently developed ductal carcinomas in situ had 64% slow-proliferating ERalpha(+)RFP(+)Erbb2(+) cells, 15% fast-proliferating ERalpha(-)RFP(+)Erbb2(+) cells derived from ERalpha(+)RFP(+)Erbb2(+) cells, and 20% fast-proliferating ERalpha(-)RFP(-)Erbb2(+) cells. The advanced tumors had mostly ERalpha(-)RFP(+)Erbb2(+) and ERalpha(-)RFP(-)Erbb2(+) cells and only a very small population of ERalpha(+)RFP(+)Erbb2(+) cells. In ERalpha(-)RFP(+)Erbb2(+) cells, GATA3 and FoxA1 decreased expression and ERalpha promoter regions became methylated, consistent with the loss of ERalpha expression. Lung metastases consisted of mostly ERalpha(-)RFP(+)Erbb2(+) cells, a few ERalpha(-)RFP(-)Erbb2(+) cells, and no ERalpha(+)RFP(+)Erbb2(+) cells. The high metastatic capacity of ERalpha(-)RFP(+)Erbb2(+) cells was associated with ERK1/2 activation. These results show that the slow-proliferating, nonmetastatic ERalpha(+)RFP(+)Erbb2(+) cells progressively lose ERalpha during tumorigenesis to become fast-proliferating, highly metastatic ERalpha(-)RFP(+)Erbb2(+) cells. The ERalpha(-)Erbb2(+) BrCs with an ERalpha(+) origin are more aggressive than those ERalpha(-)Erbb2(+) BrCs with an ERalpha(-) origin, and thus, they should be distinguished and treated differently in the future. |
