Abstract P3-03-03: Inflammatory breast cancer exhibits amplification and transcriptional activation of MYC in conjunction with NOTCH and TGFβ signaling

Abstract

Abstract Inflammatory breast cancer (IBC) is an aggressive and poorly characterized breast cancer subtype with few targets available for molecular therapy. Several attempts aimed at characterizing the disease at the genomic, transcriptomic and proteomic level. Together, these studies suggest that MYC is central to the biology of IBC. Here, we analyzed data sets from patient samples and preclinical models to corroborate this hypothesis. Genomic and transcriptomic profiles were obtained using next-generation sequencing and Affymetrix GeneChip analysis on a series of 101 and 137 samples from patients with IBC. In addition, non-IBC (nIBC) control samples were included from our own repositories (N=252) as well as from publicly available data sets (i.e. TCGA and METABRIC). Finally, RNA-sequencing and peptide phosphorylation data from preclinical IBC and nIBC models, both with and without TGFβ treatment, were explored. Apart from TP53 and ERBB2, MYC is the 3rd most frequently mutated gene with single nucleotide variants, indels and amplifications found in 22% of 101 patients. Furthermore, MYC mutations are mutually exclusive with alterations in the NOTCH genes (i.e. NOTCH1, -2, -3, and -4 and CREBBP). At the gene expression level, a MYC activation score is elevated in IBC as compare to nIBC and correlates with a NOTCH activation signature. Genes overexpressed in IBC are enriched for various sets of MYC target genes and are associated with MYC amplifications in TCGA and METABRIC samples. In preclinical models, MYC target genes are particularly responsive to TGFβ treatment in IBC cells but not in nIBC cells and analysis of peptide phosphorylation patterns suggest this interaction may be regulated via PTK2B. The present data suggest that MYC could be an important driver of IBC biology, which corroborates with the recent observation that MYC is an important hub in the signal transduction network of SUM149 and -190 cells. Furthermore, our data reveal that MYC activation is linked to NOCTH and TGFβ signaling. In earlier studies it was demonstrated that lymphovascular tumor emboli in the Mary-X mouse model of IBC exhibit NOTCH3 addition with downstream MYC overexpression, indicating that NOTCH/MYC signaling could be crucial for metastatic progression in IBC. In this context, it should be noted that an allele associated with metastatic risk in IBC patients resides at the 8q24 locus that harbors the MYC gene. Citation Format: Charlotte Rypens, François Bertucci, Patrice Viens, John WM Martens, Marcel Smid, Carolien Schröder, Naoto T Ueno, Massimo Cristofanilli, Piet Dirix, Peter Vermeulen, Luc Dirix, Steven Van Laere. Inflammatory breast cancer exhibits amplification and transcriptional activation of MYC in conjunction with NOTCH and TGFβ signaling [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-03-03.