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Prolactin induces ERα-positive and ERα-negative mammary cancer in transgenic mice

Oncogene volume 22, pages 4664–4674 (2003)Cite this article

Abstract

The role of prolactin in human breast cancer has been controversial. However, it is now apparent that human mammary epithelial cells can synthesize prolactin endogenously, permitting autocrine/paracrine actions within the mammary gland that are independent of pituitary prolactin. To model this local mammary production of prolactin (PRL), we have generated mice that overexpress prolactin within mammary epithelial cells under the control of a hormonally nonresponsive promoter, neu-related lipocalin (NRL). In each of the two examined NRL-PRL transgenic mouse lineages, female virgin mice display mammary developmental abnormalities, mammary intraepithelial neoplasias, and invasive neoplasms. Prolactin increases proliferation in morphologically normal alveoli and ducts, as well as in lesions. The tumors are of varied histotype, but papillary adenocarcinomas and adenosquamous neoplasms predominate. Neoplasms can be separated into two populations: one is estrogen receptor alpha (ERα) positive (greater than 15% of the cells stain for ERα), and the other is ERα− (<3%). ERα expression does not correlate with tumor histotype, or proliferative or apoptotic indices. These studies provide a mouse model of hormonally dependent breast cancer, and, perhaps most strikingly, a model in which some neoplasms retain ERα, as occurs in the human disease.

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Abbreviations

DCIS:

ductal carcinoma in situ

E2:

estradiol

ERα:

estrogen receptor alpha

PRL:

prolactin

MT:

metallothionein

MIN:

mammary intraepithelial neoplasia

NRL:

neu-related lipocalin

References

  • Ackler S, Ahmad S, Tobias C, Johnson MD and Glazer RI . (2002). Oncogene, 21, 198–206.

  • Amundadottir LT, Merlino G and Dickson RB . (1996). Breast Cancer Res. Treat., 39, 119–135.

  • Beck MT, Peirce SK and Chen WY . (2002). Oncogene, 21, 5047–5055.

  • Ben-Jonathan N, Mershon JL, Allen DL and Steinmetz RW . (1996). Endocr. Rev., 17, 639–669.

  • Bera TK, Hwang S, Swanson SM, Guzman RC, Edery M and Nandi S . (1994). Mol. Cell. Biochem., 132, 145–149.

  • Boot LM, Muhlbock O and Ropcke G . (1962). Gen. Comp. Endocrinol., 2, 601–603.

  • Brinster RL, Chen HY, Trumbauer ME, Yagle MK and Palmiter RD . (1985). Proc. Natl. Acad. Sci. USA, 82, 4438–4442.

  • Brisken C, Kaur S, Chavarria TE, Binart N, Sutherland RL, Weinberg RA, Kelly PA and Ormandy CJ . (1999). Dev. Biol., 210, 96–106.

  • Brockman JL, Schroeder MD and Schuler LA . (2002). Mol. Endocrinol., 16, 774–784.

  • Camarillo IG, Thordarson G, Moffat JG, Van Horn KM, Binart N, Kelly PA and Talamantes F . (2001). J. Endocrinol., 171, 85–95.

  • Cardiff RD, Anver MR, Gusterson BA, Hennighausen L, Jensen RA, Merino MJ, Rehm S, Russo J, Tavassoli FA, Wakefield LM, Ward JM and Green JE . (2000). Oncogene, 19, 968–988.

  • Christov K, Swanson SM, Guzman RC, Thordarson G, Jin E, Talamantes F and Nandi S . (1993). Carcinogenesis, 14, 2019–2025.

  • Christov KT, Guzman RC, Swanson SM, Thordarson G, Talamantes F and Nandi S . (1996). Carcinogenesis, 17, 1741–1746.

  • Clarke RB, Howell A, Potten CS and Anderson E . (1997). Cancer Res., 57, 4987–4991.

  • Clevenger CV, Furth PA, Hankinson SE and Schuler LA . (2003). Endocr. Rev. 24, 1–27.

  • Cooke NE and Baxter JD . (1982). Nature, 297, 603–606.

  • DeOme KB, Faulkin LJ, Bern HA and Blair PB . (1959). Cancer Res., 19, 515–520.

  • Edery M, Imagawa W, Larson L and Nandi S . (1985). Endocrinology, 116, 105–112.

  • Evan GI and Vousden KH . (2001). Nature, 411, 342–348.

  • Goffin V, Touraine P, Pichard C, Bernichtein S and Kelly PA . (1999). Mol. Cell. Endocrinol., 151, 79–87.

  • Gout PW, Beer CT and Noble RL . (1980). Cancer Res., 40, 2433–2436.

  • Green JE, Shibata MA, Yoshidome K, Liu ML, Jorcyk C, Anver MR, Wigginton J, Wiltrout R, Shibata E, Kaczmarczyk S, Wang W, Liu ZY, Calvo A and Couldrey C . (2000). Oncogene, 19, 1020–1027.

  • Grimm SL, Seagroves TN, Kabotyanski EB, Hovey RC, Vonderhaar BK, Lydon JP, Miyoshi K, Hennighausen L, Ormandy CJ, Lee AV, Stull MA, Wood TL and Rosen JM . (2002). Mol. Endocrinol., 16, 2675–2691.

  • Grippo PJ and Sandgren EP . (2000). Am. J. Pathol., 157, 805–813.

  • Hankinson SE, Willett WC, Michaud S, Manson JE, Colditz GA, Longcope C, Rosner B and Speizer FE . (1999). J. Natl. Cancer Inst., 91, 629–634.

  • Horseman ND, Zhao WZ, Montecino-Rodriguez E, Tanaka M, Nakashima K, Engle SJ, Smith F, Markoff E and Dorshkind K . (1997). EMBO J., 16, 6926–6935.

  • Hovey RC, Trott JF, Ginsburg E, Goldhar A, Sasaki MM, Fountain SJ, Sundararajan K and Vonderhaar BK . (2001). Dev. Dyn., 222, 192–205.

  • Hu Z-Z, Meng J and Dufau ML . (2001). J. Biol. Chem., 276, 41086–41094.

  • Humphreys RC and Hennighausen L . (1999). Cell Growth Differ., 10, 685–694.

  • Huseby RA, Soares MJ and Talamantes F . (1985). Endocrinology, 116, 1440–1448.

  • Imagawa W, Pedchenko VK, Helber J and Zhang HZ . (2002). J. Steroid Biochem. Mol. Biol., 80, 213–230.

  • Jamerson MH, Johnson MD and Dickson RB . (2000). Oncogene, 19, 1065–1071.

  • Mahler JF, Stokes W, Mann PC, Takaoka M and Maronpot RR . (1996). Toxicol. Pathol., 24, 710–716.

  • Medina D . (2002). Biochim. Biophys. Acta, 1603, 1.

  • Mertani HC, Garcia-Caballero T, Lambert A, Gérard F, Palayer C, Boutin JM, Vonderhaar BK, Waters MJ, Lobie PE and Morel G . (1998). Int. J. Cancer, 79, 202–211.

  • Muldoon TG . (1987). Endocrinology, 121, 141–149.

  • O’Neal KD and Yu-Lee L . (1994). J. Biol. Chem., 269, 26076–26082.

  • Ormandy CJ, Camus A, Barra J, Damotte D, Lucas B, Buteau H, Edery M, Brousse N, Babinet C, Binart N and Kelly PA . (1997a). Genes Dev., 11, 167–178.

  • Ormandy CJ, Hall RE, Manning DL, Robertson JFR, Blamey RW, Kelly PA, Nicholson RI and Sutherland RL . (1997b). J. Clin. Endocrinol. Metab., 82, 3692–3699.

  • Otten AD, Sanders MM and McKnight GS . (1988). Mol. Endocrinol., 2, 143–147.

  • Qin W, Golovkina TV, Peng T, Nepomnaschy I, Buggiano V, Piazzon I and Ross SR . (1999). J. Virol., 73, 368–376.

  • Reynolds C, Montone KT, Powell CM, Tomaszewski JE and Clevenger CV . (1997). Endocrinology, 138, 5555–5560.

  • Rose-Hellekant TA, Gilchrist K and Sandgren EP . (2002). Am. J. Pathol., 161, 1439–1447.

  • Rosner A, Miyoshi K, Landesman-Bollag E, Xu X, Seldin DC, Moser AR, MacLeod CL, Shyamala G, Gillgrass AE and Cardiff RD . (2002). Am. J. Pathol., 161, 1087–1097.

  • Russo J, Ao X, Grill C and Russo IH . (1999). Breast Cancer Res. Treat., 53, 217–227.

  • Schroeder MD, Rose-Hellekant T, Sandgren EP and Schuler LA . (2001). Mol. Cell. Endocrinol., 175, 173–183.

  • Schroeder MD, Symowicz J and Schuler LA . (2002). Mol. Endocrinol., 16, 45–57.

  • Schwertfeger KL, Richert MM and Anderson SM . (2001). Mol. Endocrinol., 15, 867–881.

  • Shafie S and Brooks SC . (1977). Cancer Res., 37, 792–799.

  • Shiu RPC, Elsholtz HP, Tanaka T, Friesen HG, Gout PW, Beer CT and Noble RL . (1983). Endocrinology, 113, 159–165.

  • Shoker BS, Jarvis C, Clarke RB, Anderson E, Hewlett J, Davies MP, Sibson DR and Sloane JP . (1999). Am. J. Pathol., 155, 1811–1815.

  • Shyamala G, Chou YC, Louie SG, Guzman RC, Smith GH and Nandi S . (2002). J. Steroid Biochem. Mol. Biol., 80, 137–148.

  • Silberstein GB . (2001). Breast Cancer Res., 3, 218–223.

  • Stoesz SP and Gould MN . (1995). Oncogene, 11, 2233–2241.

  • Touraine P, Martini JF, Zafrani B, Durand JC, Labaille F, Malet C, Nicolas A, Trivin C, Postel-Vinay MC, Kuttenn F and Kelly PA . (1998). J. Clin. Endocrinol. Metab., 83, 667–674.

  • Tseng YH, Kessler MA and Schuler LA . (1997). Mol. Cell. Endocrinol., 128, 117–127.

  • Vomachka AJ, Pratt SL, Lockefeer JA and Horseman ND . (2000). Oncogene, 19, 1077–1084.

  • Vonderhaar BK . (2000). Endocrine Oncology Ethier SP (ed). Humana Press: Totowa, NJ, pp. 101–120.

    Google Scholar 

  • Welsch CW and Nagasawa H . (1977). Cancer Res., 37, 951–963.

  • Wennbo H, Gebre-Medhin M, Gritli-Linde A, Ohlsson C, Isaksson OGP and Törnell J . (1997). J. Clin. Invest., 100, 2744–2751.

  • Wennbo H and Törnell J . (2000). Oncogene, 19, 1072–1076.

  • Wiseman BS and Werb Z . (2002). Science, 296, 1046–1049.

  • Yarus S, Hadsell D and Rosen JM . (1996). Genet. Eng., 18, 57–81.

  • Yoshidome K, Shibata MA, Couldrey C, Korach KS and Green JE . (2000). Cancer Res., 60, 6901–6910.

  • Yu-Lee L . (1990). Mol. Cell. Endocrinol., 68, 21–28.

  • Zeps N, Bentel JM, Papadimitriou JM, D'Antuono MF and Dawkins HJ . (1998). Differentiation, 62, 221–226.

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Acknowledgements

We are grateful to Dr Jan Lohse for generation of transgenic mice, Kristin Wentworth and Sarah Nikolai for assistance with mouse colony management and data collection, Jennifer Gutzman for her assistance with the Nb2 cell assay, and Drs Michael Gould and Kai-Shun Chen for providing the NRL gene promoter. These studies were supported by National Institutes of Health Grants R01 CA78312 (to LAS), K01 RR00145 (to TAR-H), R01-CA64843 (to EPS), T32-AG00265 and the University of Wisconsin Center for Women's Health and Women's Health Research.

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Authors and Affiliations

  1. Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Dr., Madison, 53706, WI, USA

    Teresa A Rose-Hellekant & Eric P Sandgren

  2. Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Dr., Madison, 53706, WI, USA

    Lisa M Arendt, Matthew D Schroeder & Linda A Schuler

  3. Department of Pathology and Laboratory Medicine, School of Medicine, University of Wisconsin, Madison, 53706, WI, USA

    Kennedy Gilchrist

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  1. Teresa A Rose-Hellekant
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  6. Linda A Schuler
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Correspondence to Linda A Schuler.

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Rose-Hellekant, T., Arendt, L., Schroeder, M. et al. Prolactin induces ERα-positive and ERα-negative mammary cancer in transgenic mice. Oncogene 22, 4664–4674 (2003). https://doi.org/10.1038/sj.onc.1206619

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