A role for the TGFbeta-Par6 polarity pathway in breast cancer progression.
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.
Viloria-Petit
Alicia M
AM
Center for Systems Biology, Samuel Lunenfeld Research Institute, Room 1078 Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5.
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
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence / Q000379:methods; D009362:Neoplasm Metastasis; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C499657:PARD6A protein, human; C518597:Par6 protein, mouse; D016212:Transforming Growth Factor beta