Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 33, Pages 14028-14033Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0906796106
Keywords
epithelial-to-mesenchymal transition; cell polarity; metastasis; tumor invasion; epithelial plasticity
Categories
Funding
- Canadian Institutes of Health Research (CIHR)
- Canadian Breast Cancer Research Alliance [74692]
- National Cancer Institute
- National Institutes of Health [RFA CA-95-011]
- Canadian Institutes of Health Research
- Fondation Pour La Recherche Medicale, France
- Breast Cancer Family Registry
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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.
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