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

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

Automated summary

This study reveals that ERα*RFP*Erbb2* cells progressively lose ERα during tumorigenesis to become highly metastatic, and these ERα*origin breast cancers are more aggressive.