Extrinsic and intrinsic regulation of breast epithelial plasticity and survival

Epithelial to mesenchymal transition (EMT) is a critical event in cancer progression and is closely linked to the breast epithelial cancer stem cell phenotype. Given the close interaction between the vascular endothelium and cancer cells, especially at the invasive front, we asked whether endothelial cells might play a role in EMT. Using a 3D culture model we demonstrate that endothelial cells are potent inducers of EMT in D492 an immortalized breast epithelial cell line with stem cell properties. Endothelial induced mesenchymal-like cells (D492M) derived from D492, show reduced expression of keratins, a switch from E-Cadherin (E-Cad) to N-Cadherin (N-Cad) and enhanced migration. Acquisition of cancer stem cell associated characteristics like increased CD44/CD24 ratio, resistance to apoptosis and anchorage independent growth was also seen in D492M cells. Endothelial induced EMT in D492 was partially blocked by inhibition of HGF signaling. Basallike breast cancer, a vascular rich cancer with stem cell properties and adverse prognosis has been linked with EMT. We immunostained several basal-like breast cancer samples for endothelial and EMT markers. Cancer cells close to the vascular rich areas show no or decreased expression of E-Cad and increased N-Cad expression suggesting EMT. Collectively, we have shown in a 3D culture model that endothelial cells are potent inducers of EMT in breast epithelial cells with stem cell properties. Furthermore, we demonstrate that basal-like breast cancer contains cells with an EMT phenotype, most prominently close to vascular rich areas of these tumors. We conclude that endothelial cells are potent inducers of EMT and may play a role in progression of basal-like breast cancer. Citation: Sigurdsson V, Hilmarsdottir B, Sigmundsdottir H, Fridriksdottir AJR, Ringnér M, et al. (2011) Endothelial Induced EMT in Breast Epithelial Cells with Stem Cell Properties. PLoS ONE 6(9): e23833. doi:10.1371/journal.pone. 0023833 Editor: Alexander Swarbrick, Garvan Institute of Medical Research, Australia Received March 27, 2011; Accepted July 25, 2011; Published September 6, 2011 Copyright: 2011 Sigurdsson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from Landspitali University Hospital Research Fund, University of Iceland Research Fund (www.hi.is/ research_degrees), Science and Technology Policy Council-Thematic program in postgenomic biomedicine (www.rannis.is), Science and Technology Policy Council Research fund (TG, MKM), European Science Foundation (EuroCORES program, EuroSTELLS) (TG). ‘‘Göngum saman’’, a supporting group for breast cancer research in Iceland (www.gongumsaman.is) (VS). Nordforsk, the Nordic Research Board (www.nordforsk.org), Nordic Stem Cell Mobility Program (HS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: tgudjons@hi.is