Abstract P1-06-13: Periostin controls cytokine production to maintain breast cancer stem cells

Abstract

Abstract Recent evidence suggests that the molecular heterogeneity inherent to breast cancer, which underlies metastasis, resistance to treatment and disease recurrence, can be driven by a distinct subpopulation of tumor cells referred to as cancer stem cells (CSCs). Basal-like breast cancer represents a particularly aggressive disease subtype and the tumor cells share phenotypic similarities to breast cancer stem cells. However, the extracellular cues and intracellular pathways that CSCs rely on remain unclear. Working with a breast cancer progression model system we found the invasive breast cancer cell line to exhibit numerous stem-like characteristics. Gene expression profiling, along with a careful review of the literature, identified a secreted extracellular matrix molecule, periostin (POSTN), which we hypothesized to be required for the maintenance of a cancer stem cell state. POSTN expression was increased in numerous basal-like breast cancer cell lines, as well as in cells grown as mammospheres and in the CD44+/CD24- fraction of tumor cells. Furthermore, CSC-like lines displayed increased surface levels of the integrin alpha-v beta-3 heterodimer, a known receptor for POSTN, suggesting that hyperactivation of a POSTN signaling axis could potentially regulate the CSC state. Using stable cell lines expressing an shRNA directed at POSTN or ITGB3 we have found that POSTN signaling is required for efficient mammosphere formation and for the maintenance of an ALDH-positive CSC population. Disruption of this signaling axis resulted in decreased production of cytokines, including IL-6 and IL-8 - known regulators of CSCs - as well as downstream STAT3 signaling. Furthermore, high POSTN expression is associated with a worse clinical prognosis in ER-negative breast cancer. Therefore, we suggest that POSTN signaling through integrin receptors may enrich for highly tumorigenic breast CSCs in a subset of basal-like tumors, leading to aggressive and recurrent malignancies. This reveals a previously unknown link between POSTN signaling and cytokine production, and suggests that basal-like cancers can establish a microenvironmental niche supportive of cancer stem cells. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-06-13.