Uncovering the Molecular Secrets of Inflammatory Breast Cancer Biology: An Integrated Analysis of Three Distinct Affymetrix Gene Expression Datasets

Abstract

Background: Inflammatory breast cancer (IBC) is a poorly characterized form of breast cancer. So far, the results of expression profiling in IBC are inconclusive due to various reasons including limited sample size. Here, we present the integration of three Affymetrix expression datasets collected through the World IBC Consortium allowing us to interrogate the molecular profile of IBC using the largest series of IBC samples ever reported.Experimental Design: Affymetrix profiles (HGU133-series) from 137 patients with IBC and 252 patients with non-IBC (nIBC) were analyzed using unsupervised and supervised techniques. Samples were classified according to the molecular subtypes using the PAM50-algorithm. Regression models were used to delineate IBC-specific and molecular subtype-independent changes in gene expression, pathway, and transcription factor activation.Results: Four robust IBC-sample clusters were identified, associated with the different molecular subtypes (P < 0.001), all of which were identified in IBC with a similar prevalence as in nIBC, except for the luminal A subtype (19% vs. 42%; P < 0.001) and the HER2-enriched subtype (22% vs. 9%; P < 0.001). Supervised analysis identified and validated an IBC-specific, molecular subtype-independent 79-gene signature, which held independent prognostic value in a series of 871 nIBCs. Functional analysis revealed attenuated TGF-b signaling in IBC.Conclusion: We show that IBC is transcriptionally heterogeneous and that all molecular subtypes described in nIBC are detectable in IBC, albeit with a different frequency. The molecular profile of IBC, bearing molecular traits of aggressive breast tumor biology, shows attenuation of TGF-b signaling, potentially explaining the metastatic potential of IBC tumor cells in an unexpected manner. Clin Cancer Res; 19(17); 4685-96. Ó2013 AACR.

Risk Factors for Inflammatory Breast Cancer and Other Invasive Breast Cancers

“…Obesity has been related to inflammatory processes (20). In fact, inflammation and immune-related processes characterized the IBC tumor phenotype in an analysis of IBC's molecular profile (21). Moreover e-cadherin, which is overexpressed in IBC and accounts for the formation of tumor emboli, is increased in inflammation (22).…”

Genomic and Immunological Tumor Profiling Identifies Targetable Pathways and Extensive CD8+/PDL1+ Immune Infiltration in Inflammatory Breast Cancer Tumors

“…Previous molecular profiling studies indicate that IBC is a molecularly distinct subtype of breast cancer, providing preliminary insight into clinically relevant pathways that influence IBC tumorigenesis (10). For example, HER2 is commonly amplified or overexpressed in IBC (11), whereas genes typically overexpessed in non-IBC: TGFb, progesterone receptor, and the estrogen receptor (ER) are typically downregulated in IBC (12). While previous biomarker studies offer insight into IBC, IBC analyses are typically limited to a subset of target molecules or pathways.…”

Pathological Response and Circulating Tumor Cell Count Identifies Treated HER2+ Inflammatory Breast Cancer Patients with Excellent Prognosis: BEVERLY-2 Survival Data

“…No consistent gene signature associated with IBC has been validated (4). Recently, it has been showed that IBC is transcriptionally heterogeneous and that all molecular subtypes described in non-IBC are detectable in IBC, albeit with a different frequency (5).…”