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

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Viloria-Petit A. M., David L., Jia J. Y., Erdemir T., Bane A. L., Pinnaduwage D., ...More

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol.106, no.33, pp.14028-14033, 2009 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 106 Issue: 33
  • Publication Date: 2009
  • Doi Number: 10.1073/pnas.0906796106
  • Journal Name: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.14028-14033
  • Keywords: epithelial-to-mesenchymal transition, cell polarity, metastasis, tumor invasion, epithelial plasticity, GROWTH-FACTOR-BETA, EPITHELIAL-MESENCHYMAL TRANSITION, TGF-BETA, PROTEIN PAR6, MAMMARY-TUMOR, CELL POLARITY, METASTASIS, RECEPTOR, PROLIFERATION, TUMORIGENESIS
  • Karadeniz Technical University Affiliated: No

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 beta, plays a role in breast cancer metastasis. Interference with Par6 signaling blocked TGF beta-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.