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

Menée à l'aide de modèles murins de cancer mammaire et du traçage de cellules, cette étude met en évidence un lien entre la perte de l'expression du récepteur ER alpha et l'apparition d'un sous-type de cancer du sein agressif

Résumé en anglais

HER2+ breast cancers (BrCs) are heterogeneous, but they are treated as a single type. Using a mouse model with Erbb2 (the rodent homolog of HER2)-induced BrC and cell lineage-tracing capacity, we found that ERα+Erbb2+ cancer cells proliferate slowly and are nonmetastatic but then progressively lose ERα expression to become fast proliferating and highly metastatic ERα−Erbb2+ cancer cells. ERα−Erbb2+ cancer cells with an ERα− origin proliferate fast, but they metastasize weakly. These findings suggest: 1) ERα expression should be preserved in ERα+HER2+ BrCs to restrict growth and metastasis; 2) ERα−HER2+ BrCs contain a highly metastatic subtype with an ERα+ origin and a weakly metastatic subtype with an ERα− origin, indicating a future need to identify and differentially treat these two subtypes.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.The FASTQ file for RNA-Seq data has been deposited in the BioProject category of the NCBI Sequence Read Archive database, accession no. PRJNA713819 (27). All other study data are included in the article and/or supporting information.