Abstract 1165: Focal adhesion kinase (FAK) mediates fibroblast-induced HER2+ breast cancer cell migration and invasion through a mechanism involving Stat3

In this study, we have investigated the metastatic responses of HER2+ breast cancer cells to fibroblasts and whether FAK is involved in these events. Conditioned medium derived from human lung fibroblast MRC-5 cells was used to stimulate Her2+ SKBr3 breast cancer cells in the presence or absence of FAK inhibitor, PF271, or after FAK gene knockdown, prior to determining changes in migration (Boyden Chamber assay), 3d matrix invasion, growth and FAK-mediated signalling. To compare the role of FAK with HER2 in these cells, the HER2 targeted agent, trastuzumab was additionally employed. Whilst fibroblast-conditioned medium (FCM) did not affect the growth of SKBr3 cells or their HER2- negative, ER+ counterparts MCF7 cells, FCM significantly stimulated SKBr3 cell migration (∼10 fold vs control) and promoted invasive dissociation of 3d SKBr3 cultures. FCM treatment of SKBr3 cells resulted in rapid (within 5 minutes) activation of MAPK and AKT and increased phosphorylation of the HER4 receptor and FAK (Y861). FCM also promoted an increase in STAT3 (Y704) activity with an accompanying re-distribution to sites of membrane ruffling and to the nucleus. Pharmacological inhibition of FAK, or FAK siRNA, in SKBr3 cells attenuated FCM-mediated FAK activity and suppressed STAT3 activation and subcellular re-distribution and increased the expression of E-Cadherin. Correspondingly, FCM treatment of PF271 or FAKsiRNA- treated SKBr3 cells poorly elicited migratory and invasive responses. Importa...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Tumor Biology Source Type: research