Unraveling the biology of inflammatory breast cancer through multi-omics approaches
Despite breast cancer being the most frequently diagnosed cancer in women worldwide, inflammatory breast cancer (IBC) is a rare and less known subtype. Its aggressive development is responsible for a disproportionally high amount of breast cancer-related deaths. It remains unclear what exactly distinguishes the clinicopathologic manifestations of IBC from non-IBC (nIBC). We aimed to gain a more profound understanding of IBC biology at different “omic” levels in the three chapters of this thesis. First, we investigated the role of the TGF-β pathway in IBC, building on published data showing that a molecular basis of IBC exists and is possibly shaped by an altered TGF-β signaling. We have demonstrated that IBC cells are characterized by attenuated SMAD3/SMAD4 protein expression and transcriptional activity impacting the cell motility-inducing capacity of TGFβ1. The data described in this paper provides a potential model for the disseminative and metastatic characteristics of IBC cells. To further unravel the signal transduction mechanisms that orchestrate the differential TGF-β response program in IBC and nIBC cells, we also generated peptide phosphorylation profiles of the same preclinical models treated with TGF-β1 and integrated this data with gene expression data. Four candidate mechanisms were discovered but the exact contribution of these pathways to the establishment of TGFβ resistance in IBC cells merits further investigation. Second, we performed a profound investigation of the differences between IBC and nIBC at the genomic level and confirm that IBC is distinct from non-IBC, independently from the molecular subtypes. Higher tumor mutational burden and a large set of genes more frequently altered in IBC are reported. Our data particularly supports a role for the NOTCH and DNA repair pathways in IBC biology. Moreover, a high frequency of actionable genomic alterations in IBC samples was revealed, suggesting that precision medicine is a relevant approach for this aggressive disease. Finally, we have investigated which tumor-intrinsic factors are responsible for the genuine IBC biology by molecularly characterizing available IBC preclinical models. We demonstrated that these preclinical models recapitulate to some extent the molecular features of IBC cells in patient samples, and thus constitute valuable research tools despite the lack of ER+ models. Furthermore, an important role of MYC transcriptional activity was explored and revealed interactions with ESR1 expression that are contrasting in IBC and nIBC. The data described in this paper, combined with published literature and various insights collected in this thesis suggests that IBC is a MYC-addicted tumor.
Antwerpen : University of Antwerp, Faculty of Medicine and Health Sciences , 2023
169 p.
Supervisor: van Laere, Steven [Supervisor]
Supervisor: Dirix, Luc [Supervisor]
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Creation 09.11.2023
Last edited 04.03.2024
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