Abstract 3939: The collagen receptor discoidin domain receptor 2 facilitates breast cancer metastasis by stabilizing Snail1 protein.

Abstract

Abstract Mammographic density is a leading risk factor for the development of breast cancer and these cancers are more invasive and metastatic. The increase in breast density is, in part, due to increased fibrillar collagen deposition. In an RNAi human kinome screen to identify post-transcriptional regulators of Snail1 protein stability we found the collagen receptor DDR2, but not related DDR1, to stabilize Snail1 protein as a result of collagen I activated DDR2 stimulation of ERK2 activity. This can occur independent of β1-integrin and TGFβ signals. DDR2 is not required for TGFβ-induced Epithelial Mesenchymal transition (EMT) or EMT-induced Snail1 transcription. Rather DDR2 expression, which is absent in normal breast epithelia, is induced during EMT as breast tumor cells assume invasive, mesenchymal features. DDR2-induced ERK2 activity stabilizes Snail1 protein level in two ways. First, ERK2 interacts with and phosphorylates Snail1 and second ERK2 inhibits GSK3b. DDR2 was found to be critical for breast cancer cell invasion and migration in vitro, in 3D collagen gels, and breast cancer metastasis in vivo, in syngeneic xenograft models. A majority of human invasive ductal breast carcinomas express DDR2 protein and there is a strong association between nuclear Snail1 expression, DDR2 expression, and the absence of E-cadherin expression. The small group of breast cancer patients with tumors harboring increased DDR2 gene copy number has diminished survival. We propose that DDR2 acts in a positive feedback loop to maintain Snail1 protein level and activity in breast tumor cells at the leading, invasive edge where tumor cells that have undergone EMT and invaded through the basement membrane to encounter extracellular matrix collagen I. This facilitates the continued tumor cell invasion and migration through the collagen I-rich ECM, and thereby, contributes to breast cancer metastasis. That the collagen I receptor DDR2 maintains the EMT-inducing Snail1 protein level and activity and contributes to breast cancer metastasis could explain the increase in metastasis of breast cancers in women with dense breasts. As such, DDR2 could be considered a novel RTK target for the treatment of breast cancer metastasis. Citation Format: Kun Zhang, Callie Corsa, Julie Prior, David Piwnica-Worms, Gregory D. Longmore. The collagen receptor discoidin domain receptor 2 facilitates breast cancer metastasis by stabilizing Snail1 protein. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3939. doi:10.1158/1538-7445.AM2013-3939