Abstract
One of the earliest events in epithelial carcinogenesis is the dissolution of tight junctions and cell polarity signals that are essential for normal epithelial barrier function. Here, we report that EFA6B, a guanine nucleotide exchange factor for the Ras superfamily protein Arf6 that helps assemble and stabilize tight junction, is required to maintain apico-basal cell polarity and mesenchymal phenotypes in mammary epithelial cells. In organotypic three-dimensional cell cultures, endogenous levels of EFA6B were critical to determine epithelial-mesenchymal status. EFA6B downregulation correlated with a mesenchymal phenotype and ectopic expression of EFA6B hampered TGFβ-induced epithelial-to-mesenchymal transition (EMT). Transcriptomic and immunohistochemical analyses of human breast tumors revealed that the reduced expression of EFA6B was associated with loss of tight junction components and with increased signatures of EMT, cancer stemness, and poor prognosis. Accordingly, tumors with low levels of EFA6B were enriched in the aggressive triple-negative and claudin-low breast cancer subtypes. Our results identify EFA6B as a novel antagonist in breast cancer and they point to its regulatory and signaling pathways as rational therapeutic targets in aggressive forms of this disease.
Highlights
Gene expression profiling has helped define five intrinsic tumor subtypes; essentially based on the expression of the two hormonal receptors, estrogen receptor (ER) and progesterone receptor (PR), and HER2
The MCF7-EFA6Bvsvg cells adopted characteristics of a well-differentiated apico-basal epithelial morphology: (i) regular cuboidal cells organized as a monolayer, (ii) apical punctate actin staining typical of the microvilli of polarized cells, (iii) nuclei regularly aligned basally, (iv) adherens junction proteins restricted to the lateral cell–cell contacts, (v) apical tight junction proteins (Fig. 1A and Supplementary Fig. S1A and S1B)
We have provided evidence that the tight junction regulator EFA6B acts as an antagonist to human breast cancer development
Summary
Gene expression profiling has helped define five intrinsic tumor subtypes; essentially based on the expression of the two hormonal receptors, estrogen receptor (ER) and progesterone receptor (PR), and HER2. The triple-negative breast cancer (TNBC) subtype does not express any of these receptors, rendering it unsuitable for the hormonal and anti-HER2 treatments [1]. Transcriptomic analyses have identified a new breast cancer subtype with poor prognosis named claudin-low (Cld-low), defined by the loss of expression of the proteins constitutive of the tight junction [2, 3]. This subtype, which represents 12% of total breast cancer, is 75% TNBC, characterized by a core epithelial-to-mesenchymal transition (EMT) signature, and enriched in cancer stem cells (CSC), which are associated with relative resistance to conventional anticancer treatments.
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