Depletion of beta1 integrins in triple negative breast cancer cells causes extensive alterations in gene expression profiles

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 beta1 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 disruption of beta1 integrin-mediated ECM adhesion attenuates breast tumor growth but dissemination to the lungs from such small tumors can be markedly enhanced. beta1 integrin downregulation induces compensatory upregulation of beta3 integrins, but increased beta3 expression does not lead to enhanced lung metastasis. Instead, beta1 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 TGFbeta-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 beta1 expression reinstates E-cadherin expression and cell cohesion. Moreover, restoring the network at the level of TGFbetaR, 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 beta1 integrins as cancer drug targets

ORGANISM(S): Mus musculus

SUBMITTER: John Meerman 

PROVIDER: E-MTAB-2185 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress