Abstract 1039: Downregulation of beta1 integrins in E-cadherin positive triple negative breast cancer cells elicits pro-metastatic shift in migration strategy through TGFbeta/miR200/ZEB signaling network

Abstract

Abstract Interactions with the extracellular matrix (ECM) through integrin adhesion receptors provide cancer cells with physical and chemical cues that act in concert with growth factors to support survival and proliferation. Preclinical studies testing β1 integrin antagonists in (breast) cancer models have shown inhibition of tumor growth and sensitization to radio- or chemotherapy and these strategies are currently evaluated in clinical trials. Here, we show that downregulation of β1 integrins attenuates breast tumor growth but dissemination to the lungs from such small tumors can be markedly enhanced. β1 integrin downregulation induces compensatory upregulation of β3 integrins, but increased β3 expression does not lead to enhanced lung metastasis. Instead, β1 integrin downregulation in human and mouse triple negative, E-cadherin positive breast cancer cells elicits a switch from collective invasion to individual cell migration in 3D ECM. This involves alterations in the TGFβ-BMP signaling network shifting the balance between miR-200 and ZEB, which causes a block in E-cadherin transcription. The switch is fully reversible: restored β1 expression reinstates E-cadherin expression and cell cohesion. Moreover, restoring the network at the level of TGFβR, ZEB/miR-200 balance, or E-cadherin, restores cohesion and prevents the induction of lung metastasis without affecting tumor growth. These findings reveal that integrin-mediated ECM-attachments regulate a signaling network in control of epithelial characteristics that suppress metastatic spread. This raises concerns with respect to the use of β1 integrins as cancer drug targets. Citation Format: Erik H. Danen. Downregulation of beta1 integrins in E-cadherin positive triple negative breast cancer cells elicits pro-metastatic shift in migration strategy through TGFbeta/miR200/ZEB signaling network. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1039. doi:10.1158/1538-7445.AM2014-1039