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A role for the TGFbeta-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 TGFbeta, plays a role in breast cancer metastasis. Interference with Par6 signaling blocked TGFbeta-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.

SUBMITTER: Viloria-Petit AM

PROVIDER: S-EPMC2729014 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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

Viloria-Petit Alicia M AM David Laurent L Jia Jun Yong JY Erdemir Tuba T Bane Anita L AL Pinnaduwage Dushanthi D Roncari Luba L Narimatsu Masahiro M Bose Rohit R Moffat Jason J Wong John W JW Kerbel Robert S RS O'Malley Frances P FP Andrulis Irene L IL Wrana Jeffrey L JL

Proceedings of the National Academy of Sciences of the United States of America 20090810 33

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 TGFbeta, plays a role in breast cancer metastasis. Interference with Par6 signaling blocked TGFbeta-dependent loss of polarity in acini-like structures formed by non-transformed mammary cells grown in three-dimensional structures and suppressed the pr ...[more]

PMID: 19667198

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Project description:BackgroundIn response to stress- or tissue-damage-induced apoptosis, unaffected epithelial cells undergo compensatory proliferation to maintain the integrity of the epithelium. Proximal signals regulating this response are not fully understood, but c-Jun N-terminal kinase (JNK) activity appears to be critical for both apoptosis and compensatory proliferation. Disruption of epithelial cell apical-basal polarity occurs in early cancer development and is often correlated with increased proliferation by means not fully characterized. We considered whether disruption of the various polarity complexes could provide signals identifying damaged epithelial cells and thus lead to apoptosis-induced compensatory proliferation.ResultsWe identify the Cdc42/Par6/atypical protein kinase C (aPKC) Par polarity complex as uniquely and specifically regulating apoptosis-induced compensatory proliferation in Drosophila epithelia. Genetic depletion of individual components or disruption of formation and localization of this complex, but not other polarity complexes, induces JNK-dependent apoptosis and JNK-dependent compensatory proliferation following radiation injury. When apoptosis execution is blocked, by p35 expression, Cdc42/Par6/aPKC-depleted tissues uniquely hyperproliferate, leading to tissue and organ overgrowth. Disruption of Cdc42/Par6/aPKC leads to activation of JNK through increased Rho1 and Rok activity and Rok's capacity to activate myosin but not F-actin.ConclusionsWe show that the Cdc42/Par6/aPKC polarity complex influences both a physiologic compensatory proliferation response after irradiation injury and a contrived compensatory non-cell-autonomous hyperproliferation response when cell-autonomous apoptosis, resulting from Cdc42/Par6/aPKC disruption, is inhibited. These results suggest the possibility that in cancer where apoptotic regulation is disrupted, loss of Cdc42/Par6/aPKC polarity complex organization or localization could contribute to tumor hyperproliferation and explain how polarity disruption contributes to tumor development.

Dataset Information

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

Publications

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

Similar Datasets

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