β ₁ Integrin Inhibition Elicits a Prometastatic Switch Through the TGFβ–miR-200–ZEB Network in E-Cadherin–Positive Triple-Negative Breast Cancer

Abstract

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.

miR-200a suppresses cell growth and migration by targeting MACC1 and predicts prognosis in hepatocellular carcinoma

“…Members of the miR-200 family are downregulated during progression and migration of ovarian and breast cancer, as well as in bladder, pancreatic, prostate and esophageal carcinoma. Furthermore, in several of these entities, downregulation of miR-200 is associated with reduced overall survival and poor response to chemotherapy (28)(29)(30)(31)(32)(33)(34)(35). In the present study, we found that HCC patients with low miR-200a expression had significantly worse prognosis than those with high expression of miR-200a.…”

β1 and β3 integrins in breast, prostate and pancreatic cancer: A novel implication (Review)

“…In contrast, β1 integrin may cooperate with TGF-β to enhance the expression of E-cadherin and inhibit metastasis in breast cancer (11). Additionally, downregulation of β1 integrin induces not only epithelial-to-mesenchymal transition (EMT) and anokisis resistance in cancer cells, but also the expression of MMP-9, and vascular endothelial growth factor (VEGF), promoting migration and invasion (10).…”

“…Furthermore, a previous study demonstrated that β1 integrin may also affect cell-cell junctions (11). β1 integrin may also affect the function of transforming growth factor-β (TGF-β) and regulate microRNA-200/zinc finger E-box-binding homeobox 2 to facilitate the expression of epithelial (E)-cadherin, which forms cell-cell junctions (9,11).…”

“…Furthermore, previous studies investigating the association between these two integrins have demonstrated many different perspectives (8)(9)(10)(11), together providing a novel and more comprehensive understanding of cancer.…”

Tuning Collective Cell Migration by Cell–Cell Junction Regulation

“…EMT weakens or fully dissolves cell-cell junctions between cancer cells, including AJs, desmosomes, and TJs. EMT also up-regulates the expression of stromal proteases, which cleave cadherins; deregulates integrin adhesion systems, for example, by switching b1 to b3 integrin expression and enhancing aV integrin signaling; and can redirect Rho-mediated actomyosin contractility from cell -cell junctions toward cell -matrix interactions (Kalluri and Weinberg 2009;Parvani et al 2013;Truong et al 2014). These molecular reprogramming events result in deregulated cellcell contacts, loss of apicobasal polarity, including degeneration of the lumen of otherwise ductal and glandular structures, gain of frontrear polarity, and ultimately favor the gradual transition from epithelial to mesenchymal migration modes (Bryant et al 2014).…”