Progesterone Receptor Action:

Translating Studies in Breast Cancer Models to Clinical Insights
  • Carol A. Lange
  • Carol A. Sartorius
  • Hany Abdel-Hafiz
  • Monique A. Spillman
  • Kathryn B. Horwitz
  • Britta M. Jacobsen
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 630)


Progesterone receptors (PR) are useful prognostic indicators of breast cancers likely to respond to anti-estrogen receptor (ER) therapies. However, the role of progesterone, therapeutic progestins, or unliganded or liganded PR in breast cancer development or progression remains controversial. PR are ligand-activated transcription factors that act in concert with intracellular signaling pathways as “sensors” of multiple growth factor inputs to hormonally regulated tissues, such as the breast. The recently defined induction of rapid signaling events upon progestin-binding to PR-B provides a means to ensure that receptors and coregulators are appropriately phosphorylated as part of optimal transcription complexes. PR-activated kinase cascades may provide additional avenues for progestin-regulated gene expression independent of PR nuclear action. Herein, we present an overview of progesterone/PR and signaling cross-talk in breast cancer models and discuss the potential significance of progestin/PR action in breast cancer biology using examples from both in vitro and in vivo models, as well as limited clinical data. Kinases are emerging as key mediators of PR action. Cross-talk between PR and membrane-initiated signaling events suggests a mechanism for coordinated regulation of gene subsets by mitogenic stimuli in hormonally responsive normal tissues. Dysregulation of this cross-talk mechanism may contribute to breast cancer biology; further studies are needed to address the potential for targeting PR in addition to ER and selected protein kinases as part of more effective breast cancer therapies.


Breast Cancer Breast Cancer Cell Mammary Gland Progesterone Receptor Human Breast Cancer Cell 


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  1. 1.
    Hovey RC, Trott JF, Vonderhaar BK. Establishing a framework for the functional mammary gland: from endocrinology to morphology. J Mammary Gland Biol Neoplasia 2002; 7(1):17–38.PubMedGoogle Scholar
  2. 2.
    Haslam SZ, Counterman LJ, Nummy KA. Effects of epidermal growth factor, estrogen and progestin on DNA synthesis in mammary cells in vivo are determined by the developmental state of the gland. J Cell Physiol 1993; 155(1):72–78.PubMedGoogle Scholar
  3. 3.
    Ankrapp DP, Bennett JM, Haslam SZ. Role of epidermal growth factor in the acquisition of ovarian steroid hormone responsiveness in the normal mouse mammary gland. J Cell Physiol 1998; 174(2):251–60.PubMedGoogle Scholar
  4. 4.
    Robinson GW, Hennighausen L, Johnson PF. Side-branching in the mammary gland: the progesterone-Wnt connection. Genes Dev 2000; 14(8):889–94.PubMedGoogle Scholar
  5. 5.
    Rosen JM. Hormone receptor patterning plays a critical role in normal lobuloalveolar development and breast cancer progression. Breast Dis 2003; 18:3–9.PubMedGoogle Scholar
  6. 6.
    Li Y, Rosen JM. Stem/progenitor cells in mouse mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia 2005; 10(1):17–24.PubMedGoogle Scholar
  7. 7.
    Aupperlee MD, Smith KT, Kariagina A et al. Progesterone receptor isoforms A and B: temporal and spatial differences in expression during murine mammary gland development. Endocrinology 2005; 146(8):3577–88.PubMedGoogle Scholar
  8. 8.
    Chlebowski RT, Hendrix SL, Langer RD et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 2003; 289(24):3243–53.PubMedGoogle Scholar
  9. 9.
    Haslam SZ. Experimental mouse model of hormonal therapy effects on the postmenopausal mammary gland. Breast Dis 2005; 24:71–8.PubMedGoogle Scholar
  10. 10.
    Haslam SZ, Osuch JR, Raafat AM et al. Postmenopausal hormone replacement therapy: effects on normal mammary gland in humans and in a mouse postmenopausal model. J Mammary Gland Biol Neoplasia 2002; 7(1):93–105.PubMedGoogle Scholar
  11. 11.
    Schiff R, Massarweh SA, Shou J et al. Advanced concepts in estrogen receptor biology and breast cancer endocrine resistance: implicated role of growth factor signaling and estrogen receptor coregulators. Cancer Chemother Pharmacol 2005; 56Suppl 1:10–20.PubMedGoogle Scholar
  12. 12.
    Horwitz KB, Sheridan PL, Wei LL et al. Human progesterone receptors: synthesis, structure and phosphorylation. Prog Clin Biol Res 1990; 322(41):41–52.PubMedGoogle Scholar
  13. 13.
    Jacobsen BM, Richer JK, Schittone SA et al. New human breast cancer cells to study progesterone receptor isoform ratio effects and ligand-independent gene regulation. J Biol Chem 2002; 277(31):27793–800.PubMedGoogle Scholar
  14. 14.
    Richer JK, Jacobsen BM, Manning NG et al. Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J Biol Chem 2002; 277(7):5209–18.PubMedGoogle Scholar
  15. 15.
    Mulac-Jericevic B, Lydon JP, DeMayo FJ et al. Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci USA 2003; 100(17):9744–9.PubMedGoogle Scholar
  16. 16.
    Mulac-Jericevic B, Mullinax RA, DeMayo FJ et al. Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. Science 2000; 289(5485):1751–4.PubMedGoogle Scholar
  17. 17.
    Condon JC, Hardy DB, Kovaric K et al. Up-regulation of the progesterone receptor (PR)-C isoform in laboring myometrium by activation of nuclear factor-kappaB may contribute to the onset of labor through inhibition of PR function. Mol Endocrinol 2006; 20(4):764–75.PubMedGoogle Scholar
  18. 18.
    Pratt WB, Toft DO. Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med (Maywood) 2003; 228(2):111–33.Google Scholar
  19. 19.
    Moore MR, Zhou JL, Blankenship KA et al. A sequence in the 5’ flanking region confers progestin responsiveness on the human c-myc gene. J Steroid Biochem Mol Biol 1997; 62(4):243–52.PubMedGoogle Scholar
  20. 20.
    Chalbos D, Chambon M, Ailhaud G et al. Fatty acid synthetase and its mRNA are induced by progestins in breast cancer cells. J Biol Chem 1987; 262(21):9923–6.PubMedGoogle Scholar
  21. 21.
    Krusekopf S, Chauchereau A, Milgrom E et al. Co-operation of progestational steroids with epidermal growth factor in activation of gene expression in mammary tumor cells. J Steroid Biochem Mol Biol 1991; 40(1–3):239–245.PubMedGoogle Scholar
  22. 22.
    Lange CA, Richer JK, Shen T et al. Convergence of progesterone and epidermal growth factor signaling in breast cancer. Potentiation of mitogen-activated protein kinase pathways. J Biol Chem 1998; 273(47):31308–16.PubMedGoogle Scholar
  23. 23.
    Brass AL, Barnard J, Patai BL et al. Androgen up-regulates epidermal growth factor receptor expression and binding affinity in PC3 cell lines expressing the human androgen receptor. Cancer Res 1995; 55(14):3197–203.PubMedGoogle Scholar
  24. 24.
    Church DR, Lee E, Thompson TA et al. Induction of AP-1 activity by androgen activation of the androgen receptor in LNCaP human prostate carcinoma cells. Prostate 2005; 63(2):155–68.PubMedGoogle Scholar
  25. 25.
    Richer JK, Lange CA, Manning NG et al. Convergence of progesterone with growth factor and cytokine signaling in breast cancer. Progesterone receptors regulate signal transducers and activators of transcription expression and activity. J Biol Chem 1998; 273(47):31317–26.PubMedGoogle Scholar
  26. 26.
    Gregory CW, Johnson RT Jr, Presnell SC et al. Androgen receptor regulation of G1 cyclin and cyclin-dependent kinase function in the CWR22 human prostate cancer xenograft. J Androl 2001; 22(4):537–48.PubMedGoogle Scholar
  27. 27.
    Groshong SD, Owen GI, Grimison B et al. Biphasic regulation of breast cancer cell growth by progesterone: role of the cyclin-dependent kinase inhibitors, p21 and p27 (Kip1). Mol Endocrinol 1997; 11(11):1593–607.PubMedGoogle Scholar
  28. 28.
    Owen GI, Richer JK, Tung L et al. Progesterone regulates transcription of the p21 (WAF1) cyclindependent kinase inhibitor gene through Sp1 and CBP/p300 J Biol Chem 1998; 273(17):10696–701.PubMedGoogle Scholar
  29. 29.
    Tseng L, Tang M, Wang Z et al. Progesterone receptor (hPR) upregulates the fibronectin promoter activity in human decidual fibroblasts. DNA Cell Biol 2003; 22(10):633–40.PubMedGoogle Scholar
  30. 30.
    Proietti C, Salatino M, Rosemblit C et al. Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak-and Src-dependent mechanism in breast cancer cells. Mol Cell Biol 2005; 25(12):4826–40.PubMedGoogle Scholar
  31. 31.
    McKenna NJ, O’Malley BW. Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 2002; 108(4):465–74.PubMedGoogle Scholar
  32. 32.
    Takimoto G, Horwitz K. Progesterone receptor phosphorylation—Complexities in defining a functional role. Trends Endocriool Metab 1993; 4:1–7.Google Scholar
  33. 33.
    Lange CA. Making sense of cross-talk between steroid hormone receptors and intracellular signaling pathways: who will have the last word? Mol Endocrinol 2004; 18(2):269–78.PubMedGoogle Scholar
  34. 34.
    Zhang Y, Beck CA, Poletti A et al. Phosphorylation of human progesterone receptor by cyclin-dependent kinase 2 on three sites that are authentic basal phosphorylation sites in vivo. Mol Endocrinol 1997; 11(6):823–32.PubMedGoogle Scholar
  35. 35.
    Zhang Y, Beck CA, Poletti A et al. Identification of a group of Ser-Pro motif hormone-inducible phosphorylation sites in the human progesterone receptor. Mol Endocrinol 1995; 9(8):1029–40.PubMedGoogle Scholar
  36. 36.
    Zhang Y, Beck CA, Poletti A et al. Identification of phosphorylation sites unique to the B form of human progesterone receptor. In vitro phosphorylation by casein kinase II. J Biol Chem 1994; 269(49):31034–40.PubMedGoogle Scholar
  37. 37.
    Lange CA, Shen T, Horwitz KB. Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26S proteasome. Proc Natl Acad Sci USA 2000; 97(3):1032–7.PubMedGoogle Scholar
  38. 38.
    Shen T, Horwitz KB, Lange CA. Transcriptional hyperactivity of human progesterone receptors is coupled to their ligand-dependent down-regulation by mitogen-activated proteinkinase-dependent phosphorylation of serine 294. Mol Cell Biol 2001; 21(18):6122–31.PubMedGoogle Scholar
  39. 39.
    Qiu M, Olsen A, Faivre E. Mitogen-activated protein kinase regulates nuclear association of human progesterone receptors. Mol Endocrinol 2003; 17(4):628–42.PubMedGoogle Scholar
  40. 40.
    Knotts TA, Orkiszewski RS, Cook RG et al. Identification of a phosphorylation site in the hinge region of the human progesterone receptor and additional amino-terminal phosphorylation sites. J Biol Chem 2001; 276(11):8475–83.PubMedGoogle Scholar
  41. 41.
    Font de Mora J, Brown M. AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor. Mol Cell Biol 2000; 20(14):5041–7.Google Scholar
  42. 42.
    Narayanan R, Adigun AA, Edwards DP et al. Cyclin-dependent kinase activity is required for progesterone receptor function: novel role for cyclin A/Cdk2 as a progesterone receptor coactivator. Mol Cell Biol 2005; 25(1):264–77.PubMedGoogle Scholar
  43. 43.
    Labriola L, Salatino M, Proietti CJ et al. Heregulin induces transcriptional activation of the progesterone receptor by a mechanism that requires functional ErbB-2 and mitogen-activated protein kinase activation in breast cancer cells. Mol Cell Biol 2003; 23(3):1095–111.PubMedGoogle Scholar
  44. 44.
    Pierson-Mullany LK, Lange CA. Phosphorylation of progesterone receptor serine 400 mediates ligand-independent transcriptional activity in response to activation of cyclin-dependent protein kinase 2. Mol Cell Biol 2004; 24(24):10542–57.PubMedGoogle Scholar
  45. 45.
    Takimoto GS, Hovland AR, Tasset DM et al. Role of phosphorylation on DNA binding and transcriptional functions of human progesterone receptors. J Biol Chem 1996; 271(23):13308–16.PubMedGoogle Scholar
  46. 46.
    Takimoto GS, Tasset DM, Eppert AC et al. Hormone-induced progesterone receptor phosphorylation consists of sequential DNA-independent and DNA-dependent stages: analysis with zinc finger mutants and the progesterone antagonist ZK98299. Proc Natl Acad Sci USA 1992; 89(7):3050–4.PubMedGoogle Scholar
  47. 47.
    Migliaccio A, Di Domenico M, Green S et al. Phosphorylation on tyrosine of in vitro synthesized human estrogen receptor activates its hormone binding. Mol Endocrinol 1989; 3(7):1061–1069.PubMedGoogle Scholar
  48. 48.
    Ali S, Metzger D, Bornert JM et al. Modulation of transcriptional activation by ligand-dependent phosphorylation of the human oestrogen receptor A/B region. EMBO J 1993; 12(3):1150–1160.Google Scholar
  49. 49.
    Qiu M, Lange CA. MAP kinases couple multiple functions of human progesterone receptors: degradation, transcriptional synergy and nuclear association. J Steroid Biochem Mol Biol 2003; 85:147–157.PubMedGoogle Scholar
  50. 50.
    Narayanan R, Edwards DP, Weigel NL. Human progesterone receptor displays cell cycle-dependent changes in transcriptional activity. Mol Cell Biol 2005; 25(8):2885–98.PubMedGoogle Scholar
  51. 51.
    Nardulli AM, Katzenellenbogen BS. Progesterone receptor regulation in T47D human breast cancer cells: analysis by density labeling of progesterone receptor synthesis and degradation and their modulation by progestin. Endocrinology 1988; 122(4):1532–1540.PubMedGoogle Scholar
  52. 52.
    Daniel AR, Qiu M, Faivre EJ et al. Linkage of progestin and epidermal growth factor signaling: phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth. Steroids 2007; 72(2):188–201.PubMedGoogle Scholar
  53. 53.
    Migliaccio A, Piccolo D, Castoria G et al. Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross-talk with estrogen receptor. EMBO J 1998; 17(7):2008–18.PubMedGoogle Scholar
  54. 54.
    Boonyaratanakornkit V, Scott MP, Ribon V et al. Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases. Mol Cell 2001; 8(2):269–80.PubMedGoogle Scholar
  55. 55.
    Migliaccio A, Di Domenico M, Castoria G et al. Tyrosine kinase/p21 ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells. EMBO J 1996; 15(6):1292–300.PubMedGoogle Scholar
  56. 56.
    Ballare C, Uhrig M, Bechtold T et al. Two domains of the progesterone receptor interact with the estrogen receptor and are required for progesterone activation of the c-Src/Erk pathway in mammalian cells. Mol Cell Biol 2003; 23(6):1994–2008.PubMedGoogle Scholar
  57. 57.
    Wong C, McNally C, Nickbarg E et al. Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade. Proc Natl Acad Sci USA 2002; 99(23):14783–14788.PubMedGoogle Scholar
  58. 58.
    Zhu Y, Bond J, Thomas P. Identification, classification and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc Natl Acad Sci USA 2003; 100(5):2237–42.PubMedGoogle Scholar
  59. 59.
    Skildum A, Faivre E, Lange CA. Progesterone receptors induce cell cycle progression via activation of mitogen-activated protein kinases. Mol Endocrinol 2005; 19(2):327–39.PubMedGoogle Scholar
  60. 60.
    Murphy LO, Blenis J. MAPK signal specificity: the right place at the right time. Trends Biochem Sci 2006; 31(5):268–75.PubMedGoogle Scholar
  61. 61.
    Faivre E, Lange C. Progesterone receptors upregulate Wnt-1 to induce EGFR transactivation and c-Src-dependent sustained activation of Erk1/2 MAP Kinase in breast cancer cells. Mol Cell Biol 2006; 27(2):466–80.PubMedGoogle Scholar
  62. 62.
    Santen R, Jeng MH, Wang JP et al. Adaptive hypersensitivity to estradiol: potential mechanism for secondary hormonal responses in breast cancer patients. J Steroid Biochem Mol Biol 2001; 79(1–5):115–25.PubMedGoogle Scholar
  63. 63.
    Migliaccio A, Castoria G, Di Domenico M et al. The progesterone receptor/estradiol receptor association and the progestin-triggered S-phase entry. Ernst Schering Res Found Workshop 2005(52):39–54.PubMedGoogle Scholar
  64. 64.
    Migliaccio A, Castoria G, Di Domenico M et al. Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation. EMBO J 2000; 19(20):5406–17.PubMedGoogle Scholar
  65. 65.
    Schippinger W, Regitnig P, Dandachi N et al. Evaluation of the prognostic significance of androgen receptor expression in metastatic breast cancer. Virchows Arch 2006; 449(1):24–30.PubMedGoogle Scholar
  66. 66.
    Doane AS, Danso M, Lal P et al. An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene 2006; 29; 25(28):3994–4008.PubMedGoogle Scholar
  67. 67.
    Catherino WH, Jeng MH, Jordan VC. Norgestrel and gestodene stimulate breast cancer cell growth through an oestrogen receptor mediated mechanism. Br J Cancer 1993; 67(5):945–52.PubMedGoogle Scholar
  68. 68.
    Jeng MH, Parker CJ, Jordan VC. Estrogenic potential of progestins in oral contraceptives to stimulate human breast cancer cell proliferation. Cancer Res 1992; 52(23):6539–46.PubMedGoogle Scholar
  69. 69.
    Kalkhoven E, Kwakkenbos-Isbrucker L, de Laat SW et al. Synthetic progestins induce proliferation of breast tumor cell lines via the progesterone or estrogen receptor. Mol Cell Endocrinol 1994; 102(1–2):45–52.PubMedGoogle Scholar
  70. 70.
    van der Burg B, Kalkhoven E, Isbrucker L et al. Effects of progestins on the proliferation of estrogen-dependent human breast cancer cells under growth factor-defined conditions. J Steroid Biochem Mol Biol 1992; 42(5):457–65.PubMedGoogle Scholar
  71. 71.
    Sumida T, Itahana Y, Hamakawa H et al. Reduction of human metastatic breast cancer cell aggressiveness on introduction of either form a or B of the progesterone receptor and then treatment with progestins. Cancer Res 2004; 64(21):7886–92.PubMedGoogle Scholar
  72. 72.
    McGowan EM, Clarke CL. Effect of overexpression of progesterone receptor A on endogenous progestin-sensitive endpoints in breast cancer cells. Mol Endocrinol 1999; 13(10):1657–71.PubMedGoogle Scholar
  73. 73.
    Moore MR, Hagley RD, Hissom JR. Progestin effects on lactate dehydrogenase and growth in the human breast cancer cell line T47D. Prog Clin Biol Res 1988; 262:161–79.PubMedGoogle Scholar
  74. 74.
    Moore MR, Conover JL, Franks KM. Progestin effects on long-term growth, death and Bcl-xL in breast cancer cells. Biochem Biophys Res Commun 2000; 277(3):650–4.PubMedGoogle Scholar
  75. 75.
    Musgrove EA, Lee CS, Sutherland RL. Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor alpha, epidermal growth factor receptor, c-fos and c-myc genes. Mol Cell Biol 1991; 11(10):5032–43.PubMedGoogle Scholar
  76. 76.
    Lin VC, Woon CT, Aw SE et al. Distinct molecular pathways mediate progesterone-induced growth inhibition and focal adhesion. Endocrinology 2003; 144(12):5650–7.PubMedGoogle Scholar
  77. 77.
    Gompel A, Somai S, Chaouat M et al. Hormonal regulation of apoptosis in breast cells and tissues. Steroids 2000; 65(10–11):593–8.PubMedGoogle Scholar
  78. 78.
    Kandouz M, Lombet A, Perrot JY et al. Proapoptotic effects of antiestrogens, progestins and androgen in breast cancer cells. J Steroid Biochem Mol Biol 1999; 69(1–6):463–71.PubMedGoogle Scholar
  79. 79.
    Franke HR, Vermes I. Differential effects of progestogens on breast cancer cell lines. Maturitas 2003; 46(Suppl 1):S55–8.Google Scholar
  80. 80.
    Formby B, Wiley TS. Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53. Ann Clin Lab Sci 1998; 28(6):360–9.PubMedGoogle Scholar
  81. 81.
    Bardon S, Vignon F, Montcourrier P et al. Steroid receptor-mediated cytotoxicity of an antiestrogen and an antiprogestin in breast cancer cells. Cancer Res 1987; 47(5):1441–8.PubMedGoogle Scholar
  82. 82.
    Horwitz KB. The antiprogestin RU38 486: receptor-mediated progestin versus antiprogestin actions screened in estrogen-insensitive T47Dco human breast cancer cells. Endocrinology 1985; 116(6):2236–45.PubMedGoogle Scholar
  83. 83.
    Jacobsen BM, Schittone SA, Richer JK et al. Progesterone-independent effects of human progesterone receptors (PRs) in estrogen receptor-positive breast cancer: PR isoform-specific gene regulation and tumor biology. Mol Endocrinol 2005; 19(3):574–87.PubMedGoogle Scholar
  84. 84.
    Vares G, Ory K, Lectard B et al. Progesterone prevents radiation-induced apoptosis in breast cancer cells. Oncogene 2004; 23(26):4603–13.PubMedGoogle Scholar
  85. 85.
    Moore MR, Spence JB, Kiningham KK et al. Progestin inhibition of cell death in human breast cancer cell lines. J Steroid Biochem Mol Biol 2006; 98(4–5):218–27.PubMedGoogle Scholar
  86. 86.
    Lin VC, Eng AS, Hen NE et al. Effect of progesterone on the invasive properties and tumor growth of progesterone receptor-transfected breast cancer cells MDA-MB-231. Clin Cancer Res 2001; 7(9):2880–6.PubMedGoogle Scholar
  87. 87.
    Faivre EJ, Lange CA. Progesterone receptors upregulate Wnt-1 to induce epidermal growth factor receptor transactivation and c-Src-dependent sustained activation of Erk1/2 mitogen-activated protein kinase in breast cancer cells. Mol Cell Biol 2007; 27(2):466–80.PubMedGoogle Scholar
  88. 88.
    Shyamala G, Yang X, Cardiff RD et al. Impact of progesterone receptor on cell-fate decisions during mammary gland development. Proc Natl Acad Sci USA 2000; 97(7):3044–9.PubMedGoogle Scholar
  89. 89.
    Shyamala G, Yang X, Silberstein G et al. Transgenic mice carrying an imbalance in the native ratio of A to B forms of progesterone receptor exhibit developmental abnormalities in mammary glands. Proc Natl Acad Sci USA 1998; 95(2):696–701.PubMedGoogle Scholar
  90. 90.
    Jacobsen BM, Richer JK, Sartorius CA et al. Expression profiling of human breast cancers and gene regulation by progesterone receptors. J Mammary Gland Biol. Neoplasia 2003; 8(3):257–68.PubMedGoogle Scholar
  91. 91.
    Leo JC, Wang SM, Guo CH et al. Gene regulation profile reveals consistent anticancer properties of progesterone in hormone-independent breast cancer cells transfected with progesterone receptor. Int J Cancer 2005; 117(4):561–8.PubMedGoogle Scholar
  92. 92.
    Ghatge RP, Jacobsen BM, Schittone SA et al. The progestational and androgenic properties of medroxy-progesterone acetate: gene regulatory overlap with dihydrotestosterone in breast cancer cells. Breast Cancer Res 2005; 7(6):R1036–50.PubMedGoogle Scholar
  93. 93.
    Graham JD, Yager ML, Hill HD et al. Altered progesterone receptor isoform expression remodels progestin responsiveness of breast cancer cells. Mol Endocrinol 2005; 19(11):2713–35.PubMedGoogle Scholar
  94. 94.
    Bakker GH, Setyono-Han B, Henkelman MS et al. Comparison of the actions of the antiprogestin mifepristone (RU486), the progestin megestrol acetate, the LHRH analog buserelin and ovariectomy in treatment of rat mammary tumors. Cancer Treat Rep 1987; 71(11):1021–7.PubMedGoogle Scholar
  95. 95.
    Bakker GH, Setyono-Han B, Portengen H et al. Endocrine and antitumor effects of combined treatment with an antiprogestin and antiestrogen or luteinizing hormone-releasing hormone agonist in female rats bearing mammary tumors. Endocrinology 1989; 125(3):1593–8.PubMedGoogle Scholar
  96. 96.
    Bakker GH, Setyono-Han B, Portengen H et al. Treatment of breast cancer with different antiprogestins: preclinical and clinical studies. J Steroid Biochem Mol Biol 1990; 37(6):789–94.PubMedGoogle Scholar
  97. 97.
    El Etreby MF, Liang Y. Effect of antiprogestins and tamoxifen on growth inhibition of MCF-7 human breast cancer cells in nude mice. Breast Cancer Res Treat 1998; 49(2):109–17.PubMedGoogle Scholar
  98. 98.
    Michna H, Schneider MR, Nishino Y et al. Antitumor activity of the antiprogestins ZK 98.299 and RU 38.486 in hormone dependent rat and mouse mammary tumors: mechanistic studies. Breast Cancer Res Treat 1989; 14(3):275–88.PubMedGoogle Scholar
  99. 99.
    Michna H, Schneider MR, Nishino Y et al. The antitumor mechanism of progesterone antagonists is a receptor mediated antiproliferative effect by induction of terminal cell death. J Steroid Biochem 1989; 34(1–6):447–53.PubMedGoogle Scholar
  100. 100.
    Nishino Y, Schneider MR, Michna H. Enhancement of the antitumor efficacy of the antiprogestin, onapristone, by combination with the antiestrogen, ICI 164384. J Cancer Res Clin Oncol 1994; 120(5):298–302.PubMedGoogle Scholar
  101. 101.
    Schneider MR, Michna H, Nishino Y et al. Antitumor activity of the progesterone antagonists ZK 98.299 and RU 38.486 in the hormone-dependent MXT mammary tumor model of the mouse and the DMBA-and the MNU-induced mammary tumor models of the rat. Eur J Cancer Clin Oncol 1989; 25(4):691–701.PubMedGoogle Scholar
  102. 102.
    Schneider MR, Michna H, Habenicht UF et al. The tumour-inhibiting potential of the progesterone antagonist Onapristone in the human mammary carcinoma T61 in nude mice. J Cancer Res Clin Oncol 1992; 118(3):187–9.PubMedGoogle Scholar
  103. 103.
    Schneider MR, Michna H, Nishino Y et al. Tumor-inhibiting potential of ZK 112.993, a new progesterone antagonist, in hormone-sensitive, experimental rodent and human mammary tumors. Anticancer Res 1990; 10(3):683–7.PubMedGoogle Scholar
  104. 104.
    Klijn JG, Setyono-Han B, Foekens JA. Progesterone antagonists and progesterone receptor modulators in the treatment of breast cancer. Steroids 2000; 65(10–11):825–30.PubMedGoogle Scholar
  105. 105.
    Sathya G, Jansen MS, Nagel SC. Identification and characterization of novel estrogen receptor-beta-sparing antiprogestins. Endocrinology 2002; 143(8):3071–82.PubMedGoogle Scholar
  106. 106.
    Clarke R. Human breast cancer cell line xenografts as models of breast cancer. The immunobiologies of recipient mice and the characteristics of several tumorigenic cell lines. Breast Cancer Res Treat 1996; 39(1):69–86.PubMedGoogle Scholar
  107. 107.
    Yue W, Wang J, Savino A et al. Effect of aromatase inhibitors on growth of mammary tumors in a nude mouse model. Cancer Res 1995; 55(14):3073–7.PubMedGoogle Scholar
  108. 108.
    Osborne CK, Coronado E, Allred DC et al. Acquired tamoxifen resistance: correlation with reduced breast tumor levels of tamoxifen and isomerization of trans-4-hydroxytamoxifen. J Natl Cancer Inst 1991; 83(20):1477–82.PubMedGoogle Scholar
  109. 109.
    Shafie SM, Grantham FH. Role of hormones in the growth and regression of human breast cancer cells (MCF-7) transplanted into athymic nude mice. J Natl Cancer Inst 1981; 67(1):51–6.PubMedGoogle Scholar
  110. 110.
    Osborne CK, Hobbs K, Clark GM. Effect of estrogens and antiestrogens on growth of human breast cancer cells in athymic nude mice. Cancer Res 1985; 45(2):584–90.PubMedGoogle Scholar
  111. 111.
    Sartorius CA, Harvell DM, Shen T et al. Progestins initiate a luminal to myoepithelial switch in estrogen-dependent human breast tumors without altering growth. Cancer Res 2005; 65(21):9779–88.PubMedGoogle Scholar
  112. 112.
    Lanari C, Molinolo AA, Pasqualini CD. Induction of mammary adenocarcinomas by medroxyprogesterone acetate in BALB/c female mice. Cancer Lett 1986; 33(2):215–23.PubMedGoogle Scholar
  113. 113.
    Lanari C, Kordon E, Molinolo A et al. Mammary adenocarcinomas induced by medroxyprogesterone acetate: hormone dependence and EGF receptors of BALB/c in vivo sublines. Int J Cancer 1989; 43(5):845–50.PubMedGoogle Scholar
  114. 114.
    Kordon E, Lanari C, Meiss R et al. Hormone dependence of a mouse mammary tumor line induced in vivo by medroxyprogesterone acetate. Breast Cancer Res Treat 1990; 17(1):33–43.PubMedGoogle Scholar
  115. 115.
    Montecchia MF, Lamb C, Molinolo AA et al. Progesterone receptor involvement in independent tumor growth in MPA-induced murine mammary adenocarcinomas. J Steroid Biochem Mol Biol 1999; 68(1–2):11–21.PubMedGoogle Scholar
  116. 116.
    Lamb CA, Helguero LA, Giulianelli S et al. Antisense oligonucleotides targeting the progesterone receptor inhibit hormone-independent breast cancer growth in mice. Breast Cancer Res 2005; 7(6): R1111–21.PubMedGoogle Scholar
  117. 117.
    Rosen EM, Fan S, Isaacs C. BRCA1 in hormonal carcinogenesis: basic and clinical research. Endocr Relat Cancer 2005; 12(3):533–48.PubMedGoogle Scholar
  118. 118.
    Rebbeck TR, Levin AM, Eisen A et al. Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 1999; 91(17):1475–9.PubMedGoogle Scholar
  119. 119.
    Gudas JM, Nguyen H, Li T et al. Hormone-dependent regulation of BRCA1 in human breast cancer cells. Cancer Res 1995; 55(20):4561–5.PubMedGoogle Scholar
  120. 120.
    Marks JR, Huper G, Vaughn JP et al. BRCA1 expression is not directly responsive to estrogen. Oncogene 1997; 14(1):115–21.PubMedGoogle Scholar
  121. 121.
    Spillman MA, Bowcock AM. BRCA1 and BRCA2 mRNA levels are coordinately elevated in human breast cancer cells in response to estrogen. Oncogene 1996; 13(8):1639–45.PubMedGoogle Scholar
  122. 122.
    Zheng WQ, Lu J, Zheng JM et al. Variation of ER status between primary and metastatic breast cancer and relationship to p53 expression. Steroids 2001; 66(12):905–10.PubMedGoogle Scholar
  123. 123.
    King TA, Gemignani ML, Li W et al. Increased progesterone receptor expression in benign epithelium of BRCA1-related breast cancers. Cancer Res 2004;64(15):5051–3.PubMedGoogle Scholar
  124. 124.
    Poole AJ, Li Y, Kim Y et al. Prevention of Brcal-mediated mammary tumorigenesis in mice by a progesterone antagonist. Science 2006; 314(5804):1467–70.PubMedGoogle Scholar
  125. 125.
    Arpino G, Weiss H, Lee AV et al. Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance. J Natl Cancer Inst 2005; 97(17):1254–61.PubMedGoogle Scholar
  126. 126.
    Grann VR, Troxel AB, Zojwalla NJ et al. Hormone receptor status and survival in a population-based cohort of patients with breast carcinoma. Cancer 2005; 103(11):2241–51.PubMedGoogle Scholar
  127. 127.
    Horwitz KB, Costlow ME, McGuire WL. MCF-7; a human breast cancer cell line with estrogen androgen, progesterone and glucocorticoid receptors. Steroids 1975; 26(6):785–95.PubMedGoogle Scholar
  128. 128.
    Bardou VJ, Arpino G, Elledge RM et al. Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol 2003; 21(10):1973–9.PubMedGoogle Scholar
  129. 129.
    Clark GM, McGuire WL, Hubay CA et al. Progesterone receptors as a prognostic factor in Stage II breast cancer. N Engl J Med 1983; 309(22):1343–7.PubMedGoogle Scholar
  130. 130.
    McGuire WL, Clark GM. The prognostic role of progesterone receptors in human breast cancer. Semin Oncol 1983; 10(4 Suppl 4):2–6.PubMedGoogle Scholar
  131. 131.
    Ravdin PM, Green S, Dorr TM et al. Prognostic significance of progesterone receptor levels in estrogen receptor-positive patients with metastatic breast cancer treated with tamoxifen: results of a prospective Southwest Oncology Group study. J Clin Oncol 1992; 10(8):1284–91.PubMedGoogle Scholar
  132. 132.
    Muss HB. Endocrine therapy for advanced breast cancer: a review. Breast Cancer Res Treat 1992; 21(1):15–26.PubMedGoogle Scholar
  133. 133.
    Osborne CK, Schiff R, Arpino G et al. Endocrine responsiveness: understanding how progesterone receptor can be used to select endocrine therapy. Breast 2005; 14(6):458–65.PubMedGoogle Scholar
  134. 134.
    Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 1998; 351(9114):1451–67.Google Scholar
  135. 135.
    Allegra JC, Lippman ME, Thompson EB et al. Estrogen receptor status: an important variable in predicting response to endocrine therapy in metastatic breast cancer. Eur J Cancer 1980; 16(3):323–31.PubMedGoogle Scholar
  136. 136.
    Horwitz KB, Alexander PS. In situ photolinked nuclear progesterone receptors of human breast cancer cells: subunit molecular weights after transformation and translocation. Endocrinology 1983; 113(6):2195–201.PubMedGoogle Scholar
  137. 137.
    Mote PA, Balleine RL, McGowan EM et al. Colocalization of progesterone receptors A and B by dual immunofluorescent histochemistry in human endometrium during the menstrual cycle. J Clin Endocrinol Metab 1999; 84(8):2963–71.PubMedGoogle Scholar
  138. 138.
    Mote PA, Bartow S, Tran N et al. Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis. Breast Cancer Res Treat 2002; 72(2):163–72.PubMedGoogle Scholar
  139. 139.
    Graham JD, Yeates C, Balleine RL et al. Characterization of progesterone receptor A and B expression in human breast cancer. Cancer Res 1995; 55(21):5063–8.PubMedGoogle Scholar
  140. 140.
    Graham JD, Yeates C, Balleine RL et al. Progesterone receptor A and B protein expression in human breast cancer. J Steroid Biochem Mol Biol 1996; 56(1–6 Spec No):93–8.PubMedGoogle Scholar
  141. 141.
    Bamberger A, Milde-Langosch K, Schulte H et al. Progesterone receptor isoforms, pr-b and pr-a, in breast cancer: correlations with clinicopathologic tumor parameters and expression of ap-1 factors. Horm Res 2000; 54(1):32–7.PubMedGoogle Scholar
  142. 142.
    Hopp TA, Weiss HL, Hilsenbeck SG et al. Progesterone Receptor (PR) A and B in Breast Cancer: PR-A Rich Tumors have poorer disease-free survival. Clin Cancer Res 2004; 10(8):2751–60.PubMedGoogle Scholar
  143. 143.
    Clemm DL, Sherman L, Boonyaratanakornkit V et al. Differential hormone-dependent phosphorylation of progesterone receptor A and B forms revealed by a phosphoserine site-specific monoclonal antibody. Mol Endocrinol 2000; 14(1):52–65.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2008

Authors and Affiliations

  • Carol A. Lange
    • 1
  • Carol A. Sartorius
    • 2
  • Hany Abdel-Hafiz
    • 2
  • Monique A. Spillman
    • 2
  • Kathryn B. Horwitz
    • 2
  • Britta M. Jacobsen
    • 2
  1. 1.Departments of Medicine (Division of Hematology, Oncology and Transplant) and PharmacologyUniversity of Minnesota Cancer CenterMinneapolisUSA
  2. 2.Departments of Medicine, Pathology, and Obstetrics and GynecologyUniversity of Colorado Health Sciences CenterAuroraUSA

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