Abstract
Emerging data suggest that p21-activated kinase 1 (Pak1), a downstream signaling molecule of the small GTPases, growth factors, and lipid signaling, is upregulated or hyperactivated in human breast cancer. Until now, however, no direct causative role had been found for Pak1 in mammary tumor formation. We therefore sought to identify the role that Pak1 plays in mammary gland tumorigenesis. Our results showed that in a transgenic mouse model, overexpression of catalytically active Pak1 leads to the development of malignant mammary tumors and to a variety of other breast lesions, including focal solid nodules, ductal hyperplasia, and mini-intraductal neoplasm and adenoma. We also found that Pak1 hyperactivation increases the stimulation of downstream proliferative signaling effectors MEK1/2 and p38-MAPK in mammary tumor epithelial cells. Moreover, in our study, we detected expression of estrogen receptor-alpha expression and progesterone receptor expression during early stages of the lesions, but their expression was lost during the cells' transition to malignant invasive tumors. Finally, we found that consistent with a role in breast tumor progression, Pak1 expression and its nuclear accumulation was increased progressively during the transition from ductal hyperplasia to ductal carcinoma in situ to adenocarcinoma in widely used multistep polyoma-middle T-antigen transgenic mice. Together, these findings provide the first direct evidence that Pak1 deregulation may be sufficient for the formation of mammary gland tumors.
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References
Adam L, Vadlamudi R, Kondapaka SB, Chernoff J, Mendelsohn J, Kumar R . (1998). J Biol Chem 273: 28238–28246.
Balasenthil S, Sahin AA, Barnes CJ, Wang RA, Pestell RG, Vadlamudi RK et al. (2004). J Biol Chem 279: 1422–1428.
Barkan D, Montagna C, Ried T, Green JE . (2004). Holland CC (ed). Mouse Models of Human Cancer. John Wiley and Sons, Inc.: Hoboken, New Jersey, pp 103–132.
Bekri S, Adelaide J, Merscher S, Grosgeorge J, Caroli-Bosc F, Perucca-Lostanlen D et al. (1997). Cytogenet Cell Genet 79: 125–131.
Bocchinfuso WP, Hively WP, Couse JF, Varmus HE, Korach KS . (1999). Cancer Res 59: 1869–1876.
Guy CT, Cardiff RD, Muller WJ . (1992). Mol Cell Biol 12: 954–961.
Knowles HJ, Phillips RM . (2001). Anticancer Res 21: 2305–2311.
Kumar R, Vadlamudi RK . (2002). J Cell Physiol 193: 133–144.
Kumar R, Wang RA . (2002). Microsc Res Tech 59: 49–57.
Li F, Adam L, Vadlamudi RK, Zhou H, Sen S, Chernoff J et al. (2002). EMBO Rep 3: 767–773.
Lin EY, Jones JG, Li P, Zhu L, Whitney KD, Muller WJ et al. (2003). Am J Pathol 163: 2113–2126.
Manser E, Leung T, Salhuddin H, Zhao ZS, Lim L . (1994). Nature 367: 40–46.
Manser E, Loo TH, Koh CG, Zhao ZS, Chen XQ, Tan L et al. (1998). Mol Cell 1: 183–192.
Medina D, Kittrel F . (2000). Ip MM and Asch BB (eds). Methods in Mammary Gland Biology and Breast Cancer Rsearch. Kluwer Academic/Plenum Publishers: New York, pp 101–110.
Medina D, Kittrell FS, Shepard A, Contreras A, Rosen JM, Lydon J . (2003). Cancer Res 63: 1067–1072.
Salh B, Marotta A, Wagey R, Sayed M, Pelech S . (2002). Int J Cancer 98: 145–154.
Schraml P, Schwerdtfeger G, Burkhalter F, Raggi A, Schmidt D, Ruffalo T et al. (2003). Am J Pathol 163: 985–992.
Sells MA, Boyd JT, Chernoff J . (1999). J Cell Biol 145: 837–849.
Sells MA, Knaus UG, Bagrodia S, Ambrose DM, Bakoch GM, Chernoff J . (1997). Curr Biol 7: 202–210.
Singh RR, Song C, Yang Z, Kumar R . (2005). J Biol Chem 280: 18130–18137.
Vadlamudi RK, Adam L, Wang RA, Mandal M, Nguyen D, Sahin A et al. (2000). J Biol Chem 275: 36238–36244.
Wang RA, Mazumdar A, Vadlamudi RK, Kumar R . (2002). EMBO J 21: 5437–5447.
Wang RA, Vadlamudi RK, Bagheri-Yarmand R, Beuvink I, Hynes NE, Kumar R . (2003). J Cell Biol 161: 583–592.
Zhao Z, Manser E, Chen X, Chong C, Leung T, Lim L . (1998). Mol Cell Biol 18: 2153–2163.
Acknowledgements
The authors thank Dr Clifton L Stephens for reading the pathological slides. This study was supported by Grants from the National Institute of Health Grants CA 90970 and CA 65746 (to RK).
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Wang, RA., Zhang, H., Balasenthil, S. et al. PAK1 hyperactivation is sufficient for mammary gland tumor formation. Oncogene 25, 2931–2936 (2006). https://doi.org/10.1038/sj.onc.1209309
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DOI: https://doi.org/10.1038/sj.onc.1209309
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