A role for the TGFβ-Par6 polarity pathway in breast cancer progression

Abstract

The role of polarity signaling in cancer metastasis is ill defined. Using two three-dimensional culture models of mammary epithelial cells and an orthotopic mouse model of breast cancer, we reveal that Par6 signaling, which is regulated directly by TGF␤, plays a role in breast cancer metastasis. Interference with Par6 signaling blocked TGF␤-dependent loss of polarity in acini-like structures formed by non-transformed mammary cells grown in three-dimensional structures and suppressed the protrusive morphology of mesenchymal-like invasive mammary tumor cells without rescuing E-cadherin expression. Moreover, blockade of Par6 signaling in an in vivo orthotopic model of metastatic breast cancer induced the formation of ZO-1-positive epithelium-like structures in the primary tumor and suppressed metastasis to the lungs. Analysis of the pathway in tissue microarrays of human breast tumors further revealed that Par6 activation correlated with markers of the basal carcinoma subtype in BRCA1-associated tumors. These studies thus reveal a key role for polarity signaling and the control of morphologic transformation in breast cancer metastasis.epithelial-to-mesenchymal transition ͉ cell polarity ͉ metastasis ͉ tumor invasion ͉ epithelial plasticity M etastasis, the spread of cancer cells from the primary tumor site to distant organs, accounts for over 90% of deaths in breast cancer patients (1). Metastasis has been associated with epithelial-to-mesenchymal transition (EMT), which is a complex manifestation of epithelial plasticity, in which polarized epithelial cells embedded in organized, stratified, or single cell layers convert into single fibroblastoid cells capable of locomotion (2). Cellular changes necessary for EMT include both morphological changes, as well as alterations in gene expression. While the role of the gene expression program associated with EMT has been well-described (3), it is unclear how the morphological changes associated with EMT specifically contribute to cancer progression and metastasis in vivo. The Par6 polarity complex localizes to the tight junction (TJ) and is an important regulator of the morphological transitions associated with epithelial cell plasticity (4). The complex is comprised of three highly conserved proteins, including Par3, Par6, and aPKC. Par6 is a core component that was initially identified as one of the six Par (for ''partitioning''-defective) proteins essential for asymmetric cell division in the C. elegans zygote, and was subsequently found to be required for asymmetric division of neuroblasts and the differentiation of oocytes in Drosophila, as well as the establishment/maintenance of apical-basal polarity and polarized migration in both Drosophila and mammalian cells. Par6-dependent control of apical-basal polarity is mediated by its interaction with Par3 and aPKC, as well as the Crumbs complex (4). Par6 is regulated directly by TGF␤ (5) and ErbB-2 receptors (6) to control epithelial cell plasticity and misregulation in expression of polarity proteins, including Scribb...

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

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Cancer Stem Cell Division: When the Rules of Asymmetry Are Broken

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The regulation of cell-cell adhesion during epithelial-mesenchymal transition, motility and tumor progression

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