Within the hierarchy of epithelial stem cells, normal progenitor cells may express regulated telomerase during renewal cycles of proliferation and differentiation. Discontinuous telomerase activity may promote increased renewal capacity of progenitor cells, while deregulated/continuous telomerase activity may promote immortalization when differentiation and/or senescent pathways are compromised. In the present work, we show that resveratrol activates, while progesterone inactivates, continuous telomerase activity within 24 h in subpopulations of human Li–Fraumeni syndrome-derived breast epithelial cells. Resveratrol results in immortalization of mixed progenitor cells with mutant p53, but not human epithelial cells with wild type p53. Our results demonstrate the potential for renewing progenitor cells with mutant p53 to immortalize after continuous telomerase expression when exposed to certain environmental compounds. Understanding the effects of telomerase modulators on endogenous telomerase activity in progenitor cells is relevant to the role of immortalization in the initiation and progression of cancer subtypes.
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Bankfalvi A, Ludwig A, de-Hesselle B, Buerger H, Buchwalow IB, Boecker W . (2004). Different proliferative activity of the glandular and myoepithelial lineages in benign and proliferative and early malignant breast diseases. Modern Path 17: 1051–1061.
Bayne S, Liu JP . (2005). Hormones and growth factors regulate telomerase activity in ageing and cancer. Mol Cell Endocrinol 240: 11–22.
Bhat KP, Kosmeder II JW, Pezzuto JM . (2001). Biological effects of resveratrol. Antioxid Redox Signa 3: 1041–1064.
Bhat KPL, Pezzuto JM . (2002). Cancer chemopreventive activity of resveratrol. Ann NY Acad Sci 957: 210–229.
Campisi J . (2005). Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120: 513–522.
Conneely OM, Jericevic BM, Lydon JP . (2003). Progesterone receptors in mammary gland development and tumorigenesis. J Mamm Gland Biol Neopl 8: 205–214.
Counter CM, Hahn WC, Wei W, Caddle SD, Beijersbergen RL, Lansdorp PM et al. (1998). Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc Natl Acad Sci USA 95: 14723–14728.
Dimri G, Band H, Band V . (2005). Mammary epithelial cell transformation: insights from cell culture and mouse models. Breast Cancer Res 7: 171–179.
Dong CK, Masutomi K, Hahn WC . (2005). Telomerase: regulation, function and transformation. Crit Rev Oncol Hematol 54: 85–93.
Dong Z . (2003). Molecular mechanism of the chemopreventive effect of resveratrol. Mutat Res 523–524: 145–150.
Fridriksdottir AJ, Villadsen R, Gudjonsson T, Petersen OW . (2005). Maintenance of cell type diversification in the human breast. J Mammary Gland Biol Neoplasia 10: 61–74.
Gusman J, Malonne H, Atassi G . (2001). A reappraisal of the potential chemopreventive and chemotherapeutic properties of resveratrol. Carcinogenesis 22: 1111–1117.
Hahn WC . (2004). Cancer: surviving on the edge. Cancer Cell 6: 215–222.
Holt SE, Shay JW . (1999). Role of telomerase in cellular proliferation and cancer. J Cell Physiol 180: 10–18.
Kim H, Farris J, Christman SA, Kong BW, Foster LK, O'Grady SM et al. (2002). Events in the immortalizing process of primary human mammary epithelial cells by the catalytic subunit of human telomerase. Biochem J 365 (Part 3): 765–772.
Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL et al. (1994). Specific association of human telomerase activity with immortal cells and cancer. Science 266: 2011–2015.
Lanzilli G, Fuggetta MP, Tricarico M, Cottarelli A, Serafino A, Falchetti R et al. (2006). Resveratrol down-regulates the growth and telomerase activity of breast cancer cells in vitro. G Int J Oncol 28: 641–648.
Le Corre L, Chalabi N, Delort L, Bignon YJ, Bernard-Gallon DJ . (2005). Resveratrol and breast cancer chemoprevention: molecular mechanisms. Mol Nutr Food Res 49: 462–471.
Lebeau J, Fouchet P, Ory K, Chevillard S . (2002). Down-regulation of telomerase activity after progesterone treatment of human breast cancer cells: essential role of cell cycle status. Anticancer Res 22: 2161–2166.
Leonhardt SA, Edwards DP . (2002). Mechanism of action of progesterone antagonists. Exp Biol Med (Maywood) 227: 969–980.
Leslie KK, Stein MP, Kumar NS, Dai D, Stephens J, Wandinger-Ness A et al. (2005). Progesterone receptor isoform identification and subcellular localization in endometrial cancer. Gyenol Oncol 96: 32–41.
Li X, O'Malley BW . (2003). Unfolding the action of progesterone receptors. J Biol Chem 278: 39261–39264.
Lim CS, Baumann CT, Htun H, Xian W, Irie M, Smith CL et al. (1999). Differential localization and activity of the A- and B-forms of the human progesterone receptor using green fluorescent protein chimeras. Mol Endocrinol 13: 366–375.
Masutomi K, Hahn WC . (2003). Telomerase and tumorigenesis. Cancer Lett 194: 163–172.
Masutomi K, Yu EY, Khurts S, Ben-Porath I, Currier JL, Metz GB et al. (2003). Telomerase maintains telomere structure in normal cells. Cell 114: 241–253.
Miloso M, Bertelli AA, Nicolini G, Tredici G . (1999). Resveratrol-induced activation of the mitogen-activated protein kinases, ERK1 and ERK2, in human neuroblastoma SH-SY5Y cells. Neurosci Lett 264: 141–144.
Moll UM, Ostermeyer AG, Haladay R, Winkfield B, Frazier M, Zambetti G . (1996). Cytoplasmic sequestration of wild-type p53 protein impairs the G1 checkpoint after DNA damage. Mol Cell Biol 16: 1126–1137.
Mote PA, Bartow S, Tran N, Clarke CL . (2002). Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis. Breast Cancer Res Treat 72: 163–172.
Nikolaev AY, Li M, Puskas N, Qin J, Gu W . (2003). Parc: a cytoplasmic anchor for p53. Cell 112: 1–2.
Ostermeyer AG, Runko E, Winkfield B, Ahn B, Moll UM . (1996). Cytoplasmically sequestered wild-type p53 protein in neuroblastoma is relocated to the nucleus by a C-terminal peptide. Proc Natl Acad Sci USA 93: 15190–15194.
Petersen OW, Gudjonsson T, Villadsen R, Bissell MJ, Ronnov-Jessen L . (2003). Epithelial progenitor cell lines as models of normal breast morphogenesis and neoplasia. Cell Prolif 36: 33–44.
Rambhatla L, Bohn SA, Stadler PB, Boyd JT, Coss RA, Sherley JL . (2001). Cellular senescence: ex vivo p53-dependent asymmetric cell kinetics. J Biomed Biotechnol 1: 28–37.
Saeki Y, Tamura K, Yamamoto Y, Hatada T, Furuyama J, Utsunomiya J . (1997). Germline p53 mutation at codon 133 in a cancer-prone family. J Mol Med 75: 50–56.
Shay JW, Wright WE . (2005). Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis 26: 867–874.
Shay JW, Tomlinson G, Piatyszek MA, Gollahon LS . (1995). Spontaneous in vitro immortalization of breast epithelial cells from a patient with Li-Fraumeni syndrome. Mol Cell Biol 15: 425–432.
Signorelli P, Ghidoni R . (2005). Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J Nutr Biochem 16: 449–466.
Stampfer MR, Garbe J, Nijjar T, Wigington D, Swisshelm K, Yaswen P . (2003). Loss of p53 function accelerates acquisition of telomerase activity in indefinite lifespan human mammary epithelial cell lines. Oncogene 22: 5238–5251.
Stingl J, Raouf A, Emerman JT, Eaves CJ . (2005). Epithelial progenitors in the normal human mammary gland. J Mammary Gland Biol Neoplasia 10: 49–59.
Sun W, Kang KS, Morita I, Trosko JE, Chang CC . (1999). High susceptibility of a human breast epithelial cell type with stem cell characteristics to telomerase activation and immortalization. Cancer Res 59: 6118–6123.
Tabata Y, Iizuka Y, Masuda NT, Shinei R, Kurihara K, Okonogi T et al. (2002). In vitro and in vivo characterization of novel nonsteroidal progesterone receptor antagonists derived from the fungal metabolite PF1092C. J Steroid Biochem Mol Biol 82: 217–223.
Tanaka M, Kyo S, Takakura M, Kanaya T, Sagawa T, Yamashita K et al. (1998). Expression of telomerase activity in human endometrium is localized to epithelial glandular cells and regulated in a menstrual phase-dependent manner correlated with cell proliferation. Am J Pathol 153: 1985–1991.
Trask D, Band V, Zajchowski DA, Yaswen P, Suh T, Sager R . (1990). Keratins as markers that distinguish normal and tumor-derived mammary epithelial cells. Proc Natl Acad Sci USA 87: 2319–2323.
Wang Z, Kyo S, Takakura M, Tanaka M, Yatabe N, Maida Y et al. (2000). Progesterone regulates human telomerase reverse transcriptase gene expression via activation of mitogen-activated protein kinase signaling pathway. Cancer Res 60: 5376–5381.
Williams CD, Boggess JF, LaMarque LR, Meyer WR, Murray MJ, Fritz MA et al. (2001). A prospective, randomized study of endometrial telomerase during the menstrual cycle. J Clin Endocrinol Metab 86: 3912–3917.
Yaswen P, Stampfer M . (2002). Molecular changes accompanying senescence and immortalization of cultured human mammary epithelial cells. Int J Biochem Cell Biol 34: 1382–1394.
Yu CC, Lo SC, Wang TC . (2001). Telomerase is regulated by protein kinase C-zeta in human nasopharyngeal cancer cells. Biochem J 355: 459–464.
Zhivotovsky B, Kroemer G . (2004). Apoptosis and genomic instability. Nature Rev Mol Cell Biol 5: 752–762.
We acknowledge Jackie Swanik for editorial comments and William Walker for technical assistance. This work was supported by NCI-NO1-CN43301, NCI-CN-05106, Lung Cancer SPORE P50 CA75907, NSCOR NNJ05HD36G and the Ted Nash Foundation.
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Pearce, V., Sherrell, J., Lou, Z. et al. Immortalization of epithelial progenitor cells mediated by resveratrol. Oncogene 27, 2365–2374 (2008). https://doi.org/10.1038/sj.onc.1210886
- breast epithelial
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