A role for the TGFβ-Par6 polarity pathway in breast cancer progression
- Alicia M. Viloria-Petita,
- Laurent Davida,1,
- Jun Yong Jiaa,1,
- Tuba Erdemira,
- Anita L. Baneb,c,d,
- Dushanthi Pinnaduwagee,
- Luba Roncaria,
- Masahiro Narimatsua,
- Rohit Bosea,f,
- Jason Moffatf,
- John W. Wongd,g,
- Robert S. Kerbelh,i,
- Frances P. O'Malleyb,d,
- Irene L. Andrulisb,c,d,f and
- Jeffrey L. Wranaa,f,2
- aCenter for Systems Biology, Samuel Lunenfeld Research Institute, Room 1078 Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5;
- bDepartment of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5;
- cFred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5;
- dDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Banting Institute, 100 College Street, Room 110, Toronto, ON, Canada M5G 1L5;
- eProsserman Centre for Health Research, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, ON, Canada M5G 1X5;
- fDepartment of Molecular Genetics, 1 King's College Circle, University of Toronto, Toronto, ON, Canada M5S 1A8;
- gDepartment of Anatomic Pathology, Room E4–32, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5;
- hMolecular and Cellular Biology, Room S-217, Sunnybrook Health Sciences Centre, Toronto, ON, Canada M4N 3M5; and
- iDepartment of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Princess Margaret Hospital, 610 University Avenue, Room 7–411, Toronto, ON, Canada M5G 2M9
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Communicated by Louis Siminovitch, Mount Sinai Hospital, Toronto, Canada, July 2, 2009
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↵1L.D. and J.Y.J. contributed equally to this work. (received for review March 6, 2009)
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 TGFβ, plays a role in breast cancer metastasis. Interference with Par6 signaling blocked TGFβ-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.
Footnotes
- 2To whom correspondence should be addressed. E-mail: wrana{at}mshri.on.ca
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Author contributions: A.M.V.-P., L.D., J.Y.J., T.E., A.L.B., D.P., M.N., R.S.K., F.P.O., I.L.A., and J.L.W. designed research; A.M.V.-P., L.D., J.Y.J., T.E., A.L.B., L.R., M.N., and F.P.O. performed research; A.M.V.-P., L.D., A.L.B., M.N., R.B., J.M., R.S.K., and I.L.A. contributed new reagents/analytic tools; A.M.V.-P., L.D., J.Y.J., T.E., A.L.B., D.P., J.W.W., F.P.O., I.L.A., and J.L.W. analyzed data; and A.M.V.-P., D.P., I.L.A., and J.L.W. wrote the paper.
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0906796106/DCSupplemental.
