Abstract 5191: Periostin signaling in 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. Breast cancer stem cells are associated with epithelial-mesenchymal transition (EMT) and the basal-like molecular subtype of tumors, exhibit a CD44+/CD24- expression profile and have an enhanced capacity to form mammospheres. However, the extracellular cues and intracellular pathways that cancer stem cells rely on remain unclear. Using a cell line model of breast cancer progression we found a carcinoma line that was enriched for cancer stem cells. Using microarray expression profiling we identified periostin, a secreted extracellular matrix protein, to be overexpressed in this cell line and numerous other basal-like cell lines. Periostin was also overexpressed in populations that were enriched for cancer stem cells through other means such as cell sorting or growth as mammospheres. Furthermore, cancer stem cell-like populations displayed increased surface levels of the alpha-v beta-3 integrin heterodimer, a known receptor for periostin, suggesting that hyperactivation of periostin signaling may be a common feature of the cancer stem cell state. In support of this, cells with high levels of alpha-v beta-3 integrin form significantly more mammospheres and exhibit an enhanced capacity for growth on soft agar, a surrogate marker of tumorigenesis. Conversely, treatment of cells with an alpha-V beta-3 inhibitory antibody decreased mammosphere formation in a dose-dependent manner. Knockdown of periostin expression does not seem to alter the proportion of CD44+/CD24- cells but it does influence their ability to grow as mammospheres and the activity of aldehyde dehydrogenase (ALDH), another marker of cancer stem cells. Finally, as periostin is a TGF-beta inducible gene, we are currently testing the role of periostin in TGF-beta induced EMT and have seen evidence for an attenuation of this process. Ongoing studies are aimed at characterizing the intracellular pathways regulated by periostin and determining the effect of periostin expression on chemotherapeutic resistance and metastasis, two properties which may be enhanced by the presence of cancer stem cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5191. doi:1538-7445.AM2012-5191