Abstract 1627: Kinase-independent function of focal adhesion kinase in lung metastasis of breast cancer

Abstract Focal adhesion kinase (FAK) has been shown to promote mammary tumorigenesis, lung metastasis and the maintenance of cancer stem cells in the MMTV-PyMT breast cancer model. Using mammary epithelial cell (MaEC)-specific FAK knockout and kinase-defective (KD) knockin mouse models, we recently demonstrated that loss of FAK kinase activity in MaECs specifically impaired luminal progenitor proliferation and alveologenesis, whereas FAK kinase-independent function was sufficient to support ductal invasion and basal mammary stem cell activity. To further elucidate this kinase-independent role of FAK in mammary tumorigenesis and lung metastasis, we established and analyzed three cohorts of PyMT mice expressing wild type FAK (Ctl-MT), KD-FAK (cKD-MT) and FAK-null (cKO-MT) in MaECs. This study revealed that both FAK deletion and KD knockin mutation in MaECs significantly suppressed mammary tumorigenesis and the content of stem-like tumor cells (CD24+CD29+CD61+). However, in contrast to cKO-MT mice that displayed diminished metastatic nodule formation in the lungs, loss of FAK kinase activity by KD knockin mutation did not affect lung metastatic nodule formation. Using a Boyden chamber assay, we further demonstrated that, unlike cKO-MT tumor cells that displayed diminished cell migration induced by fibronectin or TGFβ1 (as compared to Ctl-MT tumor cells), cKD-MT tumor cells exhibited strong fibronectin-, but not TGFβ1-induced migratory activity. Immunofluorescence of primary tumor sections also revealed that both Ctl-MT and cKD-MT tumors displayed strong ERK activation at tumor periphery, whereas cKO-MT tumors had weak ERK activation in this region. Lastly, when treated with or without paclitaxel in culture, we found that paclitaxel was able to induce strong expression of cleaved caspase 3 and p21 in cKO-MT but not Ctl-MT and cKD-MT tumor cells, suggesting a role for FAK kinase-independent function in the suppression of p21 expression and protection of apoptosis. Together, this study strongly implicates a role for FAK kinase-independent function in promoting lung metastasis. Citation Format: Ming Luo, Max S. Wicha, Jun-Lin Guan. Kinase-independent function of focal adhesion kinase in lung metastasis of breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1627.