Altered TGFβ signaling in the context of a type 2 immune response is a prerequisite for inflammatory breast cancer dissemination and metastasis.

A recent analysis of gene expression microarray data revealed that IBC is characterized by altered TGFbeta and immune signaling. In an independent analysis, we observed that IBC cell motility induced by TGFbeta is remarkably decreased as compared to subtype-matched non-IBC cells. RNA-sequencing demonstrated a particular role for SMAD3, MYC and YY1. Moreover, the roles of SMAD3 and MYC in IBC were confirmed on patient samples using an integrated analysis of gene and protein expression data. YY1 is a powerful transcriptional regulator that is able to repress SMAD3 and activate MYC. In addition, YY1 activity is associated with a type 2 polarized immune response that is characteristic for IBC. Therefore, we hypothesize that the immune response that characterizes IBC leads to YY1 activity, which in turn antagonizes SMAD3 signaling, blunting the TGFbeta response. In turn, a blunted TGFbeta response, leads to patterns of collective migration and formation of tumor emboli, which are typical for IBC. This hypothesis is central to the current research proposal.

Keywords:METASTASIS, BREAST CANCER

Disciplines:Morphological sciences, Oncology