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

ABSTRACT: 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 ERα^CreRFP-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.

SUBMITTER: Ding Y

PROVIDER: S-EPMC8166171 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Around 20% of breast cancers (BC) show ERBB2 gene amplification and overexpression of the ERBB2 tyrosine kinase receptor. They are associated with a poor prognosis but can benefit from targeted therapy. A better knowledge of these BCs, genomically and biologically heterogeneous, may help understand their behavior and design new therapeutic strategies. METHODS: We defined the high resolution genome and gene expression profiles of 54 ERBB2-amplified BCs using 244K oligonucleotide array-comparative genomic hybridization and whole-genome DNA microarrays. Expression of ERBB2, phosphorylated ERBB2, EGFR, IGF1R and FOXA1 proteins was assessed by immunohistochemistry to evaluate the functional ERBB2 status and identify co-expressions. RESULTS: First, we identified the ERBB2-C17orf37-GRB7 genomic segment as the minimal common 17q12-q21 amplicon, and CRKRS and IKZF3 as the most frequent centromeric and telomeric amplicon borders, respectively. Second, GISTIC analysis identified 17 other genome regions affected by copy number aberration (CNA) (amplifications, gains, losses). The expression of 37 genes of these regions was deregulated. Third, two types of heterogeneity were observed in ERBB2-amplified BCs. The genomic profiles of estrogen receptor-positive (ER+) and negative (ER-) ERBB2-amplified BCs were different. The WNT/?-catenin signaling pathway was involved in ER- ERBB2-amplified BCs, and PVT1 and TRPS1 were candidate oncogenes associated with ER+ ERBB2-amplified BCs. The size of the ERBB2 amplicon was different in inflammatory (IBC) and non-inflammatory BCs. ERBB2-amplified IBCs were characterized by the downregulated and upregulated mRNA expression of ten and two genes in proportion to CNA, respectively. IHC results showed (i) a linear relationship between ERBB2 gene amplification and its gene and protein expressions with a good correlation between ERBB2 expression and phosphorylation status; (ii) a potential signaling cross-talk between EGFR or IGF1R and ERBB2, which could influence response of ERBB2-positive BCs to inhibitors. FOXA1 was frequently coexpressed with ERBB2 but its expression did not impact on the outcome of patients with ERBB2-amplified tumors. CONCLUSION: We have shown that ER+ and ER- ERBB2-amplified BCs are different, distinguished ERBB2 amplicons in IBC and non-IBC, and identified genomic features that may be useful in the design of alternative therapeutical strategies.

Project description:15-25% of breast cancers (BC) show ERBB2-amplification and overexpression of the encoded ERBB2 tyrosine kinase receptor. They are associated with a poor prognosis but can benefit from targeted therapy. A better knowledge of these BCs may help understand their behavior and design new therapeutic strategies. In this study, we defined the high resolution genome and gene expression profiles of 54 ERBB2-amplified BCs using 244K oligonucleotide array-comparative genomic hybridization and whole-genome DNA microarrays. We first identified the ERBB2-C17orf37-GRB7 genomic segment as the minimal common amplicon, and CRKRS and IKZF3 as the most frequent centromeric and telomeric amplicon borders, respectively. Second, we identified 17 genome regions affected by copy number aberration (CNA). The expression of 37 genes of these regions was deregulated. Third, two types of heterogeneity were observed in ERBB2-amplified BCs. The genomic profiles of estrogen receptor-postive (ER+) and negative (ER-) ERBB2-amplified BCs were different. The WNT/Ã?-catenin signaling pathway was involved in ER- ERBB2-amplified BCs, and PVT1 and TRPS1 were candidate oncogenes associated with ER+ ERBB2-amplified BCs. The size of the ERBB2-amplicon was different in inflammatory (IBC) and non inflammatory BCs. ERBB2-amplified IBCs were characterized by the downregulated and upregulated mRNA expression of ten and two genes in proportion to CNA, respectively. We have shown that ERBB2 BCs are heterogeneous and identified genomic features that may be useful in the design of therapeutical strategies Tumor tissues were collected from 340 patients with invasive adenocarcinoma who underwent initial surgery at the Institut Paoli-Calmettes (Marseilles, France) between 1987 and 2007 (from a cohort of 2,175 patients with frozen tumor sample) and from a series of 91 Tunisian T4d tumors (TNM, UICC) treated between 1994 and 1998 at the Salah Azaiz Institute (Tunis, Tunisia). Each patient gave informed consent and the study was approved by our institutional review board. Samples were macrodissected and frozen in liquid nitrogen within 30 minutes of removal. Genomic imbalances were determined by aCGH using 244K CGH oligonucleotide microarrays (Hu-244A, Agilent Technologies). Gene expression data of 51 of the 54 BCs and 4 normal breast (NB) samples (NB1, NB2, NB3 and NB4, representing samples from 4 women and 3 commercial pools of respectively 1, 2 and 4 normal breast RNA, Clontech, Palo Alto, CA) were quantified by using whole-genome DNA microarrays (HG-U133 plus 2.0, Affymetrix).

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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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