β1 Integrin Inhibition Elicits a Prometastatic Switch Through the TGFβ–miR-200–ZEB Network in E-Cadherin–Positive Triple-Negative Breast Cancer

Although some breast cancer therapies reduce the primary tumor, they may trigger unwanted metastasis. When Treatment Promotes Metastasis In cancer, therapy aims to kill the primary tumor and prevent metastasis. Truong et al. found that although strategies blocking β1 integrin are effective at treating primary breast tumors, they may cause metastatic disease in certain patients. In E-cadherin–positive triple-negative breast cancer (TNBC) cell lines, blocking β1 integrin function by gene silencing or with antibodies induced epithelial-to-mesenchymal transition (EMT)–associated signaling and the loss of E-cadherin, enabling TNBC cells to migrate individually and invade a three-dimensional collagen matrix in culture. When injected into zebrafish, the β1 integrin–deficient cells disseminated further than the parent TNBC cells. When implanted in mice, these cells formed more lung metastases, despite producing smaller primary tumors compared with those produced by implanted parent cells. Thus, therapies targeted against β1 integrin may not be suitable for some TNBC patients. Interactions with the extracellular matrix (ECM) through integrin adhesion receptors provide cancer cells with physical and chemical cues that act together with growth factors to support survival and proliferation. Antagonists that target integrins containing the β1 subunit inhibit tumor growth and sensitize cells to irradiation or cytotoxic chemotherapy in preclinical breast cancer models and are under clinical investigation. We found that the loss of β1 integrins attenuated breast tumor growth but markedly enhanced tumor cell dissemination to the lungs. When cultured in three-dimensional ECM scaffolds, antibodies that blocked β1 integrin function or knockdown of β1 switched the migratory behavior of human and mouse E-cadherin–positive triple-negative breast cancer (TNBC) cells from collective to single cell movement. This switch involved activation of the transforming growth factor–β (TGFβ) signaling network that led to a shift in the balance between miR-200 microRNAs and the transcription factor zinc finger E-box–binding homeobox 2 (ZEB2), resulting in suppressed transcription of the gene encoding E-cadherin. Reducing the abundance of a TGFβ receptor, restoring the ZEB/miR-200 balance, or increasing the abundance of E-cadherin reestablished cohesion in β1 integrin–deficient cells and reduced dissemination to the lungs without affecting growth of the primary tumor. These findings reveal that β1 integrins control a signaling network that promotes an epithelial phenotype and suppresses dissemination and indicate that targeting β1 integrins may have undesirable effects in TNBC.