Deciphering the molecular biology of inflammatory breast cancer through molecular characterization of patient samples and preclinical models

Abstract

Inflammatory breast cancer is an aggressive subtype of breast cancer with dismal patient prognosis and a unique clinical presentation. In the past two decades, molecular profiling technologies have been used in order to gain insight into the molecular biology of IBC and to search for possible targets for treatment. Although a gene signature that accurately discriminates between IBC and nIBC patient samples and preclinical models was identified, the overall genomic and transcriptomic differences are small and ambiguous, mainly due to the limited sample sizes of the evaluated patient series and the failure to correct for confounding effects of the molecular subtypes. Nevertheless, data collected over the past 20 years by independent research groups increasingly support the existence of several IBC-specific biological characteristics. In this review, these features are classified as established, emerging and conceptual hallmarks based on the level of evidence reported in the literature. In addition, a synoptic model is proposed that integrates all hallmarks and that can explain how cancer cell intrinsic mechanisms (i.e. NF-κB activation, genomic instability, MYC-addiction, TGF-β resistance, adaptive stress response, chromatin remodeling, epithelial-to-mesenchymal transition) can contribute to the establishment of the dynamic immune microenvironment associated with IBC. It stands to reason that future research projects are needed to further refine (parts of) this model and to investigate its clinical translatability.

Keywords: Adaptive stress response; Chromatin remodeling; Epithelial-to-mesenchymal transition; Genomic instability; Immune-microenvironment; Inflammatory breast cancer; MYC-addiction; Molecular profiling; NF-κB activation; TGF-β resistance.