Abstract
BackgroundBreast cancer is a highly heterogeneous disease with multiple drivers and complex regulatory networks. Periostin (Postn) is a matricellular protein involved in a plethora of cancer types and other diseases. Postn has been shown to be involved in various processes of tumor development, such as angiogenesis, invasion, cell survival and metastasis. The expression of Postn in breast cancer cells has been correlated with a more aggressive phenotype. Despite extensive research, it remains unclear how epithelial cancer cells regulate Postn expression.MethodsUsing murine tumor models and human TMAs, we have assessed the proportion of tumor samples that have acquired Postn expression in tumor cells. Using biochemical approaches and tumor cell lines derived from Neu+ murine primary tumors, we have identified major regulators of Postn gene expression in breast cancer cell lines.ResultsHere, we show that, while the stromal compartment typically always expresses Postn, about 50% of breast tumors acquire Postn expression in the epithelial tumor cells. Furthermore, using an in vitro model, we show a cross-regulation between FGFR, TGFβ and PI3K/AKT pathways to regulate Postn expression. In HER2-positive murine breast cancer cells, we found that basic FGF can repress Postn expression through a PKC-dependent pathway, while TGFβ can induce Postn expression in a SMAD-independent manner. Postn induction following the removal of the FGF-suppressive signal is dependent on PI3K/AKT signaling.ConclusionOverall, these results reveal a novel regulatory mechanism and shed light on how breast tumor cells acquire Postn expression. This complex regulation is likely to be cell type and cancer specific as well as have important therapeutic implications.
Highlights
Breast cancer is a highly heterogeneous disease with multiple drivers and complex regulatory net‐ works
Periostin expression is acquired in a subset of breast cancers independently of subtype Postn has been shown to be expressed in the stroma of mammary tumors
The epithelial compartment has been found to express Postn in about 60% of cases and this has been correlated with poor prognosis [20]. To assess whether this pattern was observed in murine tumors, we investigated the proportion of tumors that acquired epithelial expression of Postn in multiple Human epidermal growth factor receptor 2 (HER2)+ breast cancer murine models and compared it to human tissue microarrays
Summary
Breast cancer is a highly heterogeneous disease with multiple drivers and complex regulatory net‐ works. The expression of Postn in breast cancer cells has been correlated with a more aggressive phenotype. Breast cancer is a complex and highly heterogeneous disease which is typically classified in molecular subtypes according to the expression of specific factors such as estrogen receptor (ESR1), progesterone receptor (PGR) and human epidermal growth factor. The HER2-positive subtype is characterized by an overexpression of HER2 with low or no expression of ESR1 and PGR. The prevalence of this subtype is approximately 25–30% and is strongly associated with highly metastatic disease and a poor prognosis [4]. Multiple genetic and biochemical alterations have been shown to contribute to the progression and metastasis of breast cancer regardless of their subtype. Inflammatory pathways have been demonstrated to recruit immune cells and contribute to changes in the tumor microenvironment
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