Carcinogenesis
Tumors caused by overexpression and forced activation of Stat5 in mammary epithelial cells of transgenic mice are parity-dependent and developed in aged, postestropausal females
Tali Eilon,
Bernd Groner,
Itamar Barash,
Tali Eilon
Institute of Animal Science, ARO, The Volcani Center, Bet-Dagan, Israel
Search for more papers by this authorBernd Groner
Georg Speyer Haus, Institute for Biomedical Research, Frankfurt/M, Germany
Search for more papers by this authorCorresponding Author
Itamar Barash
Institute of Animal Science, ARO, The Volcani Center, Bet-Dagan, Israel
Fax: +972-8-9475075.
Institute of Animal Science, ARO, The Volcani Center, P.O. Box 6, Bet-Dagan 50250, IsraelSearch for more papers by this authorTali Eilon,
Bernd Groner,
Itamar Barash,
Tali Eilon
Institute of Animal Science, ARO, The Volcani Center, Bet-Dagan, Israel
Search for more papers by this authorBernd Groner
Georg Speyer Haus, Institute for Biomedical Research, Frankfurt/M, Germany
Search for more papers by this authorCorresponding Author
Itamar Barash
Institute of Animal Science, ARO, The Volcani Center, Bet-Dagan, Israel
Fax: +972-8-9475075.
Institute of Animal Science, ARO, The Volcani Center, P.O. Box 6, Bet-Dagan 50250, IsraelSearch for more papers by this authorAbstract
In transgenic mice overexpressing Stat5 or a constitutively activated Stat5 variant (STAT5ca), we show for the first time that parity is required for the development of tumors in postestropausal females. Tumors were detected in glands of multiparous transgenic female mice after latency period of 14 months, but rarely in their age-matched virgin (AMV) counterparts. This period was not affected by distinguishable tumor pathologies and was not dependent upon transgenic Stat5 variant. To associate Stat5 deregulation, parity and the postestropausal tumor occurrence with mammary cancer formation, the activities of endogenous and transgenic Stat5 were measured in the glands of aged multiparous and AMV females. No differences in phosphorylated Stat5 (pStat5) levels were found between the 2 cohorts. However, promoter sequences comprising the Stat5 binding sites from the cyclin D1 or the bcl-x genes associate differentially with acetylated histone H4 in aged multiparous and AMV STAT5ca transgenic females. Individual epithelial cells varied greatly with respect to the presence of nuclear pStat5. A small subset of epithelial cells, in which pStat5 and cyclin D1 were co-expressed, was exclusively present in the multiparous glands. Changes in chromatin structure might persist past the reproductive life time of the multiparous mice and contribute to the transcription of the cyclin D1 gene by activated Stat5. This may cause the detectable expression of cyclin D1 and add to the process of tumorigenesis. © 2007 Wiley-Liss, Inc.
References
- 1 Kelsey JL, Gammon MD, John EM. Reproductive factors and breast cancer. Epidemiol Rev 1993; 15: 36–47.
- 2 Merrill RM, Fugal S, Novilla LB, Raphael MC. Cancer risk associated with early and late maternal age at first birth. Gynecol Oncol 2005; 96: 583–93.
- 3 Medina D. Mammary developmental fate and breast cancer risk. Endocr Relat Cancer 2005; 12: 483–95.
- 4 Ahlgren M, Melbye M, Wohlfahrt J, Sorensen TI. Growth patterns and the risk of breast cancer in women. N Engl J Med 2004; 351: 1619–26.
- 5 Ma H, Berenstein L, Ross RK Ursin G. Hormone-related risk factors for breast cancer in women under age 50 years by estrogen and progesterone receptor status: results from a case-control and case-case comparison. Breast Cancer Res 2006; 8: R39–R49.
- 6 Ramon JM, Escriba JM, Casas I, Benet J, Iglesias C, Gavalda L, Torras G, Oromi J. Age at first full-term pregnancy, lactation and parity and risk of breast cancer: a case-control study in Spain. Eur J Epidemiol 1996; 12: 449–53.
- 7 Lambe M, Hsieh C, Trichopoulos D, Ekbom A, Pavia M, Adami HO. Transient increase in the risk of breast cancer after giving birth. NEngl J Med 1994; 331: 5–9.
- 8 Albrektsen G, Heuch I, Hansen S, Kvale G. Breast cancer risk by age at birth, time since birth and time intervals between births: exploring interaction effects. Br J Cancer 2005; 92: 167–75.
- 9 Russo J, Russo I. H. Role of differentiation in the pathogenesis and prevention of breast cancer. Endocr Relat Cancer 1997; 4: 7–12.
- 10 Sivaraman L, Stephens LC, Markaverich BM, Clark JA, Krnacik S, Conneely OM, Medina D. Hormone-induced refractoriness to mammary carcinogenesis in Wistar-Furth rats. Carcinogenesis 1998; 19: 1573–81.
- 11 Schedin P, Mitrenga T, McDaniel S, Kaeck M. Mammary ECM composition and function are altered by reproductive state. Mol Carcinog 2004; 41: 207–20.
- 12 Sivaraman L, Hilsenbeck SG, Zhong L, Gay J, Conneely OM, Medina D, O'Malley BW. Early exposure of the rat mammary gland to estrogen and progesterone blocks co-localization of estrogen receptor expression and proliferation. J Endocrinol 2001; 171: 75–83.
- 13 Russo J, Mailo D, Hu YF, Balogh G, Sheriff F, Russo IH. Breast differentiation and its implication in cancer prevention. Clin Cancer Res 2005; 11: 931s–936s.
- 14 Russo J, Balogh GA, Chen J, Fernandez SV, Fernbaugh R, Heulings R, Mailo DA, Moral R, Russo PA, Sheriff F, Vanegas JE, Wang R, et al. The concept of stem cell in the mammary gland and its implication in morphogenesis, cancer and prevention. Front Biosci 2006; 11: 151–72.
- 15 Schedin P. Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer 2006; 6: 281–91.
- 16 Lewis MT, Ross S, Strickland PA, Sugnet CW, Jimenez E, Scott MP, Daniel CW. Defects in mouse mammary gland development caused by conditional haploinsufficiency of Patched-1. Development 1999; 126: 5181–93.
- 17 Roy PG, Thompson AM. Cyclin D1 and breast cancer. Breast 2006; 15: 718–27.
- 18 D'Cruz CM, Gunther EJ, Boxer RB, Hartman JL, Sintasath L, Moody SE, Cox JD, Ha SI, Belka GK, Golant A, Cardiff RD, Chodosh LA. c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations. Nat Med 2001; 7: 235–9.
- 19 Felty Q, Singh KP, Roy D. Estrogen-induced G1/S transition of G0-arrested estrogen-dependent breast cancer cells is regulated by mitochondrial oxidant signaling. Oncogene 2005; 24: 4883–93.
- 20 Sicinski P, Donaher JL, Parker SB, Li T, Fazeli A, Gardner H, Haslam SZ, Bronson RT, Elledge SJ, Weinberg RA. Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 1995; 82: 621–30.
- 21 Fantl V, Stamp G, Andrews A, Rosewell I, Dickson C. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev 1995; 9: 2364–72.
- 22 Sutherland RL, Musgrove EA. Cyclin D1 and mammary carcinoma: new insights from transgenic mouse models. Breast Cancer Res 2002; 4: 14–17.
- 23 Walker RA, Martin CV. The aged breast. J Pathol 2007; 211: 232–40.
- 24 Witherby SM, Muss HB. Special issues related to breast cancer adjuvant therapy in older women. Breast 2005; 14: 600–11.
- 25 Wakao H, Gouilleux F, Groner B. Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response. EMBO J 1994; 13: 2182–91.
- 26 Ihle JN, Kerr IM. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet 1995; 11: 69–74.
- 27 Darnell JE,Jr. STATs and gene regulation. Science 1997; 277: 1630–5.
- 28 Liu X, Robinson GW, Wagner KU, Garrett L, Wynshaw-Boris A, Hennighausen L. Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev 1997; 11: 179–86.
- 29 Humphreys RC, Hennighausen L. Signal transducer and activator of transcription 5a influences mammary epithelial cell survival and tumorigenesis. Cell Growth Differ 1999; 10: 685–94.
- 30 Iavnilovitch E, Groner B, Barash I. Overexpression and forced activation of stat5 in mammary gland of transgenic mice promotes cellular proliferation, enhances differentiation, and delays postlactational apoptosis. Mol Cancer Res 2002; 1: 32–47.
- 31 Iavnilovitch E, Eilon T, Groner B, Barash I. Expression of a carboxy terminally truncated Stat5 with no transactivation domain in the mammary glands of transgenic mice inhibits cell proliferation during pregnancy, delays onset of milk secretion, and induces apoptosis upon involution. Mol Reprod Dev 2006; 73: 841–9.
- 32 Iavnilovitch E, Cardiff RD, Groner B, Barash I. Deregulation of Stat5 expression and activation causes mammary tumors in transgenic mice. Int J Cancer 2004; 112: 607–19.
- 33 Kazansky AV, Raught B, Lindsey SM, Wang YF, Rosen JM. Regulation of mammary gland factor/Stat5a during mammary gland development. Mol Endocrinol 1995; 9: 1598–609.
- 34 Liu X, Robinson GW, Gouilleux F, Groner B, Hennighausen L. Cloning and expression of Stat5 and an additional homologue (Stat5b) involved in prolactin signal transduction in mouse mammary tissue. Proc Natl Acad Sci USA 1995; 92: 8831–5.
- 35 Liu X, Robinson GW, Hennighausen L. Activation of Stat5a and Stat5b by tyrosine phosphorylation is tightly linked to mammary gland differentiation. Mol Endocrinol 1996; 10: 1496–506.
- 36 Reichenstein M, Gottlieb H, Damari GM, Iavnilovitch E, Barash I. A new β-lactoglobulin-based vector targets luciferase cDNA expression to the mammary gland of transgenic mice. Transgenic Res 2001; 10: 445–56.
- 37 Barash I, Reichenstein M. Real-time imaging of β-lactoglobulin-targeted luciferase activity in the mammary glands of transgenic mice. Mol Reprod Dev 2002; 61: 42–8.
- 38 Gouilleux F, Wakao H, Mundt M, Groner B. Prolactin induces phosphorylation of Tyr694 of Stat5 (MGF), a prerequisite for DNA binding and induction of transcription. EMBO J 1994; 13: 4361–9.
- 39 Berchtold S, Moriggl R, Gouilleux F, Silvennoinen O, Beisenherz C, Pfitzner E, Wissler M, Stocklin E, Groner B. Cytokine receptor-independent, constitutively active variants of STAT5. J Biol Chem 1997; 272: 30237–43.
- 40 Reichenstein M, German T, Barash I. BLG-e1—a novel regulatory element in the distal region of the β-lactoglobulin gene promoter. FEBS Lett 2005; 579: 2097–104.
- 41 Wagner KU, Boulanger CA, Henry MD, Sgagias M, Hennighausen L, Smith GH. An adjunct mammary epithelial cell population in parous females: its role in functional adaptation and tissue renewal. Development 2002; 129: 1377–86.
- 42 Bratthauer GL, Strauss BL, Tavassoli FA. STAT 5a expression in various lesions of the breast. Virchows Arch 2006; 448: 165–71.
- 43 Struhl K. Fundamentally different logic of gene regulation in eukaryotes and prokaryotes. Cell 1999; 98: 1–4.
- 44 Muller C, Leutz A. Chromatin remodeling in development and differentiation. Curr Opin Genet Dev 2001; 11: 167–74.
- 45 Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000; 403: 41–5.
- 46 Socolovsky M, Fallon AE, Wang S, Brugnara C, Lodish HF. Fetal anemia and apoptosis of red cell progenitors in Stat5a−/−5b−/−mice: a direct role for Stat5 in Bcl-X(L) induction. Cell 1999; 98: 181–91.
- 47 Brockman JL, Schroeder MD, Schuler LA. PRL activates the cyclin D1 promoter via the Jak2/Stat pathway. Mol Endocrinol 2002; 16: 774–84.
- 48 Fernandez de Mattos S, Essafi A, Soeiro I, Pietersen AM, Birkenkamp KU, Edwards CS, Martino A, Nelson BH, Francis JM, Jones MC, Brosens JJ, Coffer PJ, et al. FoxO3a and BCR-ABL regulate cyclin D2 transcription through a STAT5/BCL6-dependent mechanism. Mol Cell Biol 2004; 24: 10058–71.
- 49 Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 2002; 8: 945–54.
- 50 Yu H, Jove R. The STATs of cancer–new molecular targets come of age. Nat Rev Cancer 2004; 4: 97–105.
- 51 Grillot DA, Gonzalez-Garcia M, Ekhterae D, Duan L, Inohara N, Ohta S, Seldin MF, Nunez G. Genomic organization, promoter region analysis, and chromosome localization of the mouse bcl-x gene. JImmunol 1997; 158: 4750–7.
- 52 Nevalainen MT, Xie J, Bubendorf L, Wagner KU, Rui H. Basal activation of transcription factor signal transducer and activator of transcription (Stat5) in nonpregnant mouse and human breast epithelium. Mol Endocrinol 2002; 16: 1108–24.
- 53 Pfitzner E, Jahne R, Wissler M, Stoecklin E, Groner B. p300/CREB-binding protein enhances the prolactin-mediated transcriptional induction through direct interaction with the transactivation domain of Stat5, but does not participate in the Stat5-mediated suppression of the glucocorticoid response. Mol Endocrinol 1998; 12: 1582–93.
- 54 Rascle A, Lees E. Chromatin acetylation and remodeling at the Cis promoter during STAT5-induced transcription. Nucleic Acids Res 2003; 31: 6882–90.
- 55 Rascle A, Lees E. Chromatin acetylation and remodeling at the Cis promoter during STAT5-induced transcription. Nucleic Acids Res 2003; 31: 6882–90.
- 56 Fukuda H, Sano N, Muto S, Horikoshi M. Simple histone acetylation plays a complex role in the regulation of gene expression. Brief Funct Genomic Proteomic 2006; 5: 190–208.
- 57 Cooper SJ, Trinklein ND, Nguyen L, Myers RM. Serum response factor binding sites differ in three human cell types. Genome Res 2007; 17: 136–44.
- 58 Liotta L, Petricoin E. Molecular profiling of human cancer. Nat Rev Genet 2000; 1: 48–56.
- 59 Sherr CJ. D-type cyclins. Trends BiochemSci 1995; 20: 187–4.
- 60 Lauper N, Beck AR, Cariou S, Richman L, Hofmann K, Reith W, Slingerland JM, Amati B. Cyclin E2: a novel CDK2 partner in the late G1 and S phases of the mammalian cell cycle. Oncogene 1998; 17: 2637–43.
- 61 Fantl V, Edwards PA, Steel JH, Vonderhaar BK, Dickson C. Impaired mammary gland development in Cyl-1(−/−) mice during pregnancy and lactation is epithelial cell autonomous. Dev Biol 1999; 212: 1–11.
- 62 Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV. Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 1994; 369: 669–71.
- 63 Boulanger CA, Wagner KU, Smith GH. Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-β1 expression. Oncogene 2005; 24: 552–60.
- 64 Schoenenberger CA, Andres AC, Groner B, van der Valk M, LeMeur M, Gerlinger P. Targeted c-myc gene expression in mammary glands of transgenic mice induces mammary tumours with constitutive milk protein gene transcription. EMBO J 1988; 7: 169–75.
- 65 Evron E, Umbricht CB, Korz D, Raman V, Loeb DM, Niranjan B, Buluwela L, Weitzman SA, Marks J, Sukumar S. Loss of cyclin D2 expression in the majority of breast cancers is associated with promoter hypermethylation. Cancer Res 2001; 61: 2782–7.
- 66 Kong G, Chua SS, Yijun Y, Kittrell F, Moraes RC, Medina D, Said TK. Functional analysis of cyclin D2 and p27(Kip1) in cyclin D2 transgenic mouse mammary gland during development. Oncogene 2002; 21: 7214–25.
- 67 Buckley MF, Sweeney KJ, Hamilton JA, Sini RL, Manning DL, Nicholson RI, defazio A, Watts CK, Musgrove EA, Sutherland RL. Expression and amplification of cyclin genes in human breast cancer. Oncogene 1993; 8: 2127–33.
- 68 Lukas J, Bartkova J, Welcker M, Petersen OW, Peters G, Strauss M, Bartek J. Cyclin D2 is a moderately oscillating nucleoprotein required for G1 phase progression in specific cell types. Oncogene 1995; 10: 2125–34.
- 69 Sutherland RL, Musgrove EA. Cyclins and breast cancer. J Mammary Gland Biol Neoplasia 2004; 9: 95–104.
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