title: Stage of breast cancer progression influences cellular response to activation of the WNT/planar cell polarity pathway.
abstract: Planar cell polarity (PCP) signaling has been shown in different studies to either promote or inhibit the malignancy of breast cancer. Using the 21T cell lines, which were derived from an individual patient and represent distinct stages of progression, we show that the prototypical PCP ligand, WNT5A, is expressed highest in 21MT-1 cells (invasive mammary carcinoma) and lowest in 21PT (atypical ductal hyperplasia) and 21NT (ductal carcinoma in situ) cells. Overexpression of WNT5A decreased spherical colony formation and increased invasion and in vivo extravasation only in 21NT cells; whereas overexpression increased migration of both 21PT and 21NT cells. WNT5A overexpression also increased RHOA expression of both cell lines and subsequent RHOA knockdown blocked WNT5A-induced migration, but only partially blocked WNT5A-induced invasion of 21NT cells. PCP can signal through VANGL1 to modulate AP-1 target genes (e.g. MMP3) and induce invasion. VANGL1 knockdown inhibited WNT5A-induced invasion of 21NT cells, but had no effect on WNT5A-induced migration of either 21PT or 21NT cells. WNT5A-induced MMP3 expression was seen only in 21NT cells, an effect that was VANGL1 dependent, but independent of AP-1. We thus provide evidence that PCP signaling can act in a context dependent manner to promote breast cancer progression.
authors.affiliation: 1] Department of Pathology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON [2] London Regional Cancer Program, London Health Sciences Centre, London, ON [3] Department of Surgery, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON.
authors.forename: Connor D
authors.initials: CD
authors.lastname: MacMillan
authors.affiliation: 1] London Regional Cancer Program, London Health Sciences Centre, London, ON [2] Department of Surgery, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON.
authors.forename: Hon S
authors.initials: HS
authors.lastname: Leong
authors.affiliation: London Regional Cancer Program, London Health Sciences Centre, London, ON.
authors.forename: David W
authors.initials: DW
authors.lastname: Dales
authors.affiliation: 1] London Regional Cancer Program, London Health Sciences Centre, London, ON [2] Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Robertson
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB.
authors.forename: John D
authors.initials: JD
authors.lastname: Lewis
authors.affiliation: 1] Department of Pathology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON [2] London Regional Cancer Program, London Health Sciences Centre, London, ON [3] Department of Oncology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON [4] Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON.
authors.forename: Ann F
authors.initials: AF
authors.lastname: Chambers
authors.affiliation: 1] Department of Pathology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON [2] London Regional Cancer Program, London Health Sciences Centre, London, ON [3] Department of Oncology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON.
authors.forename: Alan B
authors.initials: AB
authors.lastname: Tuck
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D016764:Cell Polarity / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D018450:Disease Progression; D005260:Female; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D008565:Membrane Proteins / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1 / Q000235:genetics; D051153:Wnt Proteins / Q000096:biosynthesis / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics; D000071818:Wnt-5a Protein; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; C488287:VANGL1 protein, human; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C066737:RHOA protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; D020742:rhoA GTP-Binding Protein