Abstract
Cancer is initiated by somatic mutations in oncogenes or tumor suppressor genes. However, additional alterations provide selective advantages to the tumor cells to resist treatment and develop metastases. Their identification is of paramount importance. Reduced expression of EFA6B (Exchange Factor for ARF6, B) is associated with breast cancer of poor prognosis. Here, we report that loss of EFA6B triggers a transcriptional reprogramming of the cell-to-ECM interaction machinery and unleashes CDC42-dependent collective invasion in collagen. In xenograft experiments, MCF10 DCIS.com cells, a DCIS-to-IDC transition model, invades faster when knocked-out for EFA6B. In addition, invasive and metastatic tumors isolated from patients have lower expression of EFA6B and display gene ontology signatures identical to those of EFA6B knock-out cells. Thus, we reveal an EFA6B-regulated molecular mechanism that controls the invasive potential of mammary cells; this finding opens up avenues for the treatment of invasive breast cancer.
Highlights
Cancer is initiated by somatic mutations in oncogenes or tumor suppressor genes
A slight decrease (1.4 ± 0.4 fold) of ARF6 expression was observed in EFA6BKO cells (Fig. 1a, b), which was noticed in Breast cancer (BC) patients whose EFA6B expression was decreased[7]
How the loss of EFA6B induces epithelial-to-mesenchymal transition (EMT) is an open question. It could be through disassembling cell–cell junction and release of associated transcription factors[37,38,39,40,41], loss of the permeability barrier giving growth factors access to their receptors[42,43,44], or through the remodeling of the extracellular matrix (ECM) that in turn could stimulate EMT22,45
Summary
Cancer is initiated by somatic mutations in oncogenes or tumor suppressor genes. additional alterations provide selective advantages to the tumor cells to resist treatment and develop metastases. Invasive and metastatic tumors isolated from patients have lower expression of EFA6B and display gene ontology signatures identical to those of EFA6B knock-out cells. We reveal an EFA6B-regulated molecular mechanism that controls the invasive potential of mammary cells; this finding opens up avenues for the treatment of invasive breast cancer. We found that EFA6B knock-out (KO) mammary cells undergo collective invasion in 3D-collagen This invasion is supported by the activation of an epithelial-to-mesenchymal transition (EMT) program and the alteration of ECM interaction. The expression of EFA6B is lower in invasive than in in situ tumors isolated from patients, and the invasive tumors display gene ontology signatures identical to those of EFA6B knock-out cells. We reveal an EFA6B-regulated molecular mechanism that controls the invasive potential of mammary cells; this finding opens up avenues for the treatment of invasive BC
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