Advertisement

Molecular Medicine

, Volume 21, Issue 1, pp 242–256 | Cite as

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

  • Mostafa A. Borahay
  • Ayman Al-Hendy
  • Gokhan S. Kilic
  • Darren Boehning
Review Article

Abstract

Uterine leiomyomas are the most common tumors of the female genital tract, affecting 50% to 70% of females by the age of 50. Despite their prevalence and enormous medical and economic impact, no effective medical treatment is currently available. This is, in part, due to the poor understanding of their underlying pathobiology. Although they are thought to start as a clonal proliferation of a single myometrial smooth muscle cell, these early cytogenetic alterations are considered insufficient for tumor development and additional complex signaling pathway alterations are crucial. These include steroids, growth factors, transforming growth factor-beta (TGF-β)/Smad; wingless-type (Wnt)/β-catenin, retinoic acid, vitamin D, and peroxisome proliferator-activated receptor γ (PPARγ). An important finding is that several of these pathways converge in a summative way. For example, mitogen-activated protein kinase (MAPK) and Akt pathways seem to act as signal integrators, incorporating input from several signaling pathways, including growth factors, estrogen and vitamin D. This underlines the multifactorial origin and complex nature of these tumors. In this review, we aim to dissect these pathways and discuss their interconnections, aberrations and role in leiomyoma pathobiology. We also aim to identify potential targets for development of novel therapeutics.

Notes

Acknowledgments

This work was supported, in whole or in part, by the following grants to Mostafa Borahay: NIH K12 Career Development Award 5K12HD001269-12 and an award from the Institute for Translational Sciences at the University of Texas Medical Branch supported in part by NCATS, NIH Grant CTSA UL1TR000071. This work also was supported by the following grants to Darren Boehning: NIH Grants 1R01GM081685-01 and 3R01GM081685-03S1 and startup funds provided by the University of Texas Health Science Center at Houston.

References

  1. 1.
    Okolo S. (2008) Incidence, aetiology and epidemiology of uterine fibroids. Best Pract. Res. Clin. Obstet. Gynaecol. 22:571–88.PubMedCrossRefGoogle Scholar
  2. 2.
    Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. (2003) High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am. J. Obstet. Gynecol. 188:100–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Cardozo ER, et al. The estimated annual cost of uterine leiomyomata in the United States. Am. J. Obstet. Gynecol. 206:211e1–9.CrossRefGoogle Scholar
  4. 4.
    Townsend DE, Sparkes RS, Baluda MC, McClelland G. (1970) Unicellular histogenesis of uterine leiomyomas as determined by electrophoresis by glucose-6-phosphate dehydrogenase. Am. J. Obstet. Gynecol. 107:1168–73.PubMedCrossRefGoogle Scholar
  5. 5.
    Pandis N, et al. (1991) Chromosome analysis of 96 uterine leiomyomas. Cancer Genet. Cytogenet. 55:11–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Rein MS. (2000) Advances in uterine leiomyoma research: the progesterone hypothesis. Environ. Health Perspect. 108 Suppl 5:791–3.PubMedCrossRefGoogle Scholar
  7. 7.
    Maruo T, Ohara N, Wang J, Matsuo H. (2004) Sex steroidal regulation of uterine leiomyoma growth and apoptosis. Hum. Reprod. Update. 10:207–20.PubMedCrossRefGoogle Scholar
  8. 8.
    Kim JJ, Kurita T, Bulun SE. (2013) Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer. Endocr. Rev. 34:130–62.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Lethaby A, Vollenhoven B, Sowter M. (2001) Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst. Rev. CD000547.Google Scholar
  10. 10.
    Jensen EV, DeSombre ER. (1973) Estrogen-receptor interaction. Science. 182:126–34.PubMedCrossRefGoogle Scholar
  11. 11.
    Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. (1996) Cloning of a novel receptor expressed in rat prostate and ovary. Proc. Natl. Acad. Sci. U. S. A. 93:5925–30.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Menasce LP, White GR, Harrison CJ, Boyle JM. (1993) Localization of the estrogen receptor locus (ESR) to chromosome 6q25.1 by FISH and a simple post-FISH banding technique. Genomics. 17:263–5.PubMedCrossRefGoogle Scholar
  13. 13.
    Enmark E, et al. (1997) Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern. J. Clin. Endocrinol. Metab. 82:4258–65.PubMedGoogle Scholar
  14. 14.
    Kuiper GG, et al. (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology. 138:863–70.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Dechering K, Boersma C, Mosselman S. (2000) Estrogen receptors alpha and beta: two receptors of a kind? Curr. Med. Chem. 7:561–76.PubMedCrossRefGoogle Scholar
  16. 16.
    Matthews J, Gustafsson JA. (2003) Estrogen signaling: a subtle balance between ER alpha and ER beta. Mol. Interv. 3:281–92.PubMedCrossRefGoogle Scholar
  17. 17.
    O’Dowd BF, et al. (1998) Discovery of three novel G-protein-coupled receptor genes. Genomics. 47:310–3.PubMedCrossRefGoogle Scholar
  18. 18.
    Prossnitz ER, et al. (2008) Estrogen signaling through the transmembrane G protein-coupled receptor GPR30. Annu. Rev. Physiol. 70:165–90.PubMedCrossRefGoogle Scholar
  19. 19.
    Levin ER. (2009) Plasma membrane estrogen receptors. Trends Endocrinol. Metab. 20:477–82.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Pedram A, Razandi M, Levin ER. (2006) Nature of functional estrogen receptors at the plasma membrane. Mol. Endocrinol. 20:1996–2009.PubMedCrossRefGoogle Scholar
  21. 21.
    Raam S, et al. (1983) Translocation of cytoplasmic estrogen receptors to the nucleus: immunohistochemical demonstration utilizing rabbit antibodies to estrogen receptors of mammary carcinomas. Breast Cancer Res. Treat. 3:179–99.PubMedCrossRefGoogle Scholar
  22. 22.
    Monje P, Zanello S, Holick M, Boland R. (2001) Differential cellular localization of estrogen receptor alpha in uterine and mammary cells. Mol. Cell. Endocrinol. 181:117–29.PubMedCrossRefGoogle Scholar
  23. 23.
    Knoblauch R, Garabedian MJ. (1999) Role for Hsp90-associated cochaperone p23 in estrogen receptor signal transduction. Mol. Cell. Biol. 19:3748–59.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Pratt WB, Toft DO. (2003) Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp. Biol. Med. 228:111–33.CrossRefGoogle Scholar
  25. 25.
    Klinge CM, Jernigan SC, Mattingly KA, Risinger KE, Zhang J. (2004) Estrogen response element-dependent regulation of transcriptional activation of estrogen receptors alpha and beta by coactivators and corepressors. J. Mol. Endocrinol. 33:387–410.PubMedCrossRefGoogle Scholar
  26. 26.
    Moggs JG, Orphanides G. (2001) Estrogen receptors: orchestrators of pleiotropic cellular responses. EMBO Rep. 2:775–81.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Benassayag C, et al. (1999) Estrogen receptors (ERalpha/ERbeta) in normal and pathological growth of the human myometrium: pregnancy and leiomyoma. Am. J. Physiol. 276:E1112–8.PubMedGoogle Scholar
  28. 28.
    Kovacs KA, Oszter A, Gocze PM, Kornyei JL, Szabo I. (2001) Comparative analysis of cyclin D1 and oestrogen receptor (alpha and beta) levels in human leiomyoma and adjacent myometrium. Mol. Hum. Reprod. 7:1085–91.PubMedCrossRefGoogle Scholar
  29. 29.
    Maekawa R, et al. Genome-wide DNA methylation analysis reveals a potential mechanism for the pathogenesis and development of uterine leiomyomas. PLoS One. 8:e66632.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Tian R, et al. Differential expression of G-protein-coupled estrogen receptor-30 in human myometrial and uterine leiomyoma smooth muscle. Fertil. Steril. 99:256–63.CrossRefGoogle Scholar
  31. 31.
    Hermon TL, et al. (2008) Estrogen receptor alpha (ERalpha) phospho-serine-118 is highly expressed in human uterine leiomyomas compared to matched myometrium. Virchows Arch. 453:557–69.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Barbarisi A, et al. (2001) 17-beta estradiol elicits an autocrine leiomyoma cell proliferation: evidence for a stimulation of protein kinase-dependent pathway. J. Cell. Physiol. 186:414–24.PubMedCrossRefGoogle Scholar
  33. 33.
    Nierth-Simpson EN, et al. (2009) Human uterine smooth muscle and leiomyoma cells differ in their rapid 17beta-estradiol signaling: implications for proliferation. Endocrinology. 150:2436–45.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Ishikawa H, et al. (2009) High aromatase expression in uterine leiomyoma tissues of African-American women. J. Clin. Endocrinol. Metab. 94:1752–6.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Bulun SE, Simpson ER, Word RA. (1994) Expression of the CYP19 gene and its product aromatase cytochrome P450 in human uterine leiomyoma tissues and cells in culture. J. Clin. Endocrinol. Metab 78:736–43.PubMedGoogle Scholar
  36. 36.
    Bulun SE, et al. (2005) Aromatase in endometriosis and uterine leiomyomata. J. Steroid. Biochem. Mol. Biol. 95:57–62.PubMedCrossRefGoogle Scholar
  37. 37.
    Shozu M, Murakami K, Inoue M. (2004) Aromatase and leiomyoma of the uterus. Semin. Reprod. Med. 22:51–60.PubMedCrossRefGoogle Scholar
  38. 38.
    Kasai T, et al. (2004) Increased expression of type I 17beta-hydroxysteroid dehydrogenase enhances in situ production of estradiol in uterine leiomyoma. J. Clin. Endocrinol. Metab. 89:5661–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Olive DL, Lindheim SR, Pritts EA. (2004) Non-surgical management of leiomyoma: impact on fertility. Curr. Opin. Obstet. Gynecol. 16:239–43.PubMedCrossRefGoogle Scholar
  40. 40.
    Shozu M, Murakami K, Segawa T, Kasai T, Inoue M. (2003) Successful treatment of a symptomatic uterine leiomyoma in a perimenopausal woman with a nonsteroidal aromatase inhibitor. Fertil. Steril. 79:628–31.PubMedCrossRefGoogle Scholar
  41. 41.
    Howe SR, Gottardis MM, Everitt JI, Walker C. (1995) Estrogen stimulation and tamoxifen inhibition of leiomyoma cell growth in vitro and in vivo. Endocrinology. 136:4996–5003.PubMedCrossRefGoogle Scholar
  42. 42.
    Cohen I, et al. (1994) Tamoxifen treatment in pre-menopausal breast cancer patients may be associated with ovarian overstimulation, cystic formations and fibroid overgrowth. Br. J. Cancer. 69:620–1.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Deng L, Wu T, Chen XY, Xie L, Yang J. (2012) Selective estrogen receptor modulators (SERMs) for uterine leiomyomas. Cochrane Database Syst. Rev. 10:CD005287.PubMedGoogle Scholar
  44. 44.
    Salama SA, Nasr AB, Dubey RK, Al-Hendy A. (2006) Estrogen metabolite 2-methoxyestradiol induces apoptosis and inhibits cell proliferation and collagen production in rat and human leiomyoma cells: a potential medicinal treatment for uterine fibroids. J. Soc. Gynecol. Investig. 13:542–50.PubMedCrossRefGoogle Scholar
  45. 45.
    Salama SA, et al. (2009) Catechol-o-methyltransferase expression and 2-methoxyestradiol affect micro-tubule dynamics and modify steroid receptor signaling in leiomyoma cells. PLoS One. 4:e7356.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Al-Hendy A, Lee EJ, Wang HQ, Copland JA. (2004) Gene therapy of uterine leiomyomas: adenovirus-mediated expression of dominant negative estrogen receptor inhibits tumor growth in nude mice. Am. J. Obstet. Gynecol. 191:1621–31.PubMedCrossRefGoogle Scholar
  47. 47.
    Farber M, Conrad S, Heinrichs WL, Herrmann WL. (1972) Estradiol binding by fibroid tumors and normal myometrium. Obstet. Gynecol. 40:479–86.PubMedGoogle Scholar
  48. 48.
    Puukka MJ, Kontula KK, Kauppila AJ, Janne OA, Vihko RK. (1976) Estrogen receptor in human myoma tissue. Mol. Cell. Endocrinol. 6:35–44.PubMedCrossRefGoogle Scholar
  49. 49.
    Kim JJ, Sefton EC, Bulun SE. (2009) Progesterone receptor action in leiomyoma and endometrial cancer. Prog. Mol. Biol. Transl. Sci. 87:53–85.PubMedCrossRefGoogle Scholar
  50. 50.
    Kawaguchi K, et al. (1989) Mitotic activity in uterine leiomyomas during the menstrual cycle. Am. J. Obstet. Gynecol. 160:637–41.PubMedCrossRefGoogle Scholar
  51. 51.
    Ishikawa H, et al. (2010) Progesterone is essential for maintenance and growth of uterine leiomyoma. Endocrinology. 151:2433–42.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Kastner P, et al. (1990) Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J. 9:1603–14.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Zhu Y, Bond J, Thomas P. (2003) Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc. Natl. Acad. Sci. U. S. A. 100:2237–42.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Dressing GE, Goldberg JE, Charles NJ, Schwertfeger KL, Lange CA. (2011) Membrane progesterone receptor expression in mammalian tissues: a review of regulation and physiological implications. Steroids. 76:11–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Lange CA. (2008) Integration of progesterone receptor action with rapid signaling events in breast cancer models. J. Steroid. Biochem. Mol. Biol. 108:203–12.PubMedCrossRefGoogle Scholar
  56. 56.
    Boonyaratanakornkit V, et al. (2001) Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases. Mol. Cell. 8:269–80.PubMedCrossRefGoogle Scholar
  57. 57.
    Yamada T, et al. (2004) Progesterone down-regulates insulin-like growth factor-I expression in cultured human uterine leiomyoma cells. Hum. Reprod. 19:815–21.PubMedCrossRefGoogle Scholar
  58. 58.
    Maruo T, et al. (2000) Effects of progesterone on uterine leiomyoma growth and apoptosis. Steroids. 65:585–92.PubMedCrossRefGoogle Scholar
  59. 59.
    Shimomura Y, Matsuo H, Samoto T, Maruo T. (1998) Up-regulation by progesterone of proliferating cell nuclear antigen and epidermal growth factor expression in human uterine leiomyoma. J. Clin. Endocrinol. Metab. 83:2192–8.PubMedGoogle Scholar
  60. 60.
    Hoekstra AV, et al. (2009) Progestins activate the AKT pathway in leiomyoma cells and promote survival. J. Clin. Endocrinol. Metab. 94:1768–74.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Yin P, et al. Transcription factor KLF11 integrates progesterone receptor signaling and proliferation in uterine leiomyoma cells. Cancer Res. 70:1722–30.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Fiscella K, et al. (2006) Effect of mifepristone for symptomatic leiomyomata on quality of life and uterine size: a randomized controlled trial. Obstet. Gynecol. 108:1381–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Eisinger SH, Bonfiglio T, Fiscella K, Meldrum S, Guzick DS. (2005) Twelve-month safety and efficacy of low-dose mifepristone for uterine myomas. J. Minim. Invasive Gynecol. 12:227–33.PubMedCrossRefGoogle Scholar
  64. 64.
    Donnez J, et al. (2012) Ulipristal acetate versus placebo for fibroid treatment before surgery. N. Eng. J. Med. 366:409–20.CrossRefGoogle Scholar
  65. 65.
    Ohara N, et al. (2007) Comparative effects of SPRM asoprisnil (J867) on proliferation, apoptosis, and the expression of growth factors in cultured uterine leiomyoma cells and normal myometrial cells. Reprod. Sci. 14:20–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Weinberg RA. (2007) The Biology of Cancer. New York: Garland Science.Google Scholar
  67. 67.
    Abbott A. (2009) Neuroscience: One hundred years of Rita. Nature. 458:564–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Ciarmela P, et al. (2011) Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications. Hum. Reprod. Update 17:772–90.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Marsh EE, Bulun SE. (2006) Steroid hormones and leiomyomas. Obstet. Gynecol. Clin North Am. 33:59–67.PubMedCrossRefGoogle Scholar
  70. 70.
    Islam MS, et al. (2013) Complex networks of multiple factors in the pathogenesis of uterine leiomyoma. Fertil. Steril. 100:178–93.PubMedCrossRefGoogle Scholar
  71. 71.
    Sozen I, Arici A. (2002) Interactions of cytokines, growth factors, and the extracellular matrix in the cellular biology of uterine leiomyomata. Fertil. Steril. 78:1–12.PubMedCrossRefGoogle Scholar
  72. 72.
    Burroughs KD, et al. (2002) Dysregulation of IGF-I signaling in uterine leiomyoma. J. Endocrinol. 172:83–93.PubMedCrossRefGoogle Scholar
  73. 73.
    Peng L, et al. (2009) Expression of insulin-like growth factors (IGFs) and IGF signaling: molecular complexity in uterine leiomyomas. Fertil. Steril. 91:2664–75.PubMedCrossRefGoogle Scholar
  74. 74.
    Chang CC, Hsieh YY, Lin WH, Lin CS. (2010) Leiomyoma and vascular endothelial growth factor gene polymorphisms: a systematic review. Taiwan. J. Obstet. Gynecol. 49:247–53.PubMedCrossRefGoogle Scholar
  75. 75.
    Rossi MJ, Chegini N, Masterson BJ. (1992) Presence of epidermal growth factor, platelet-derived growth factor, and their receptors in human myometrial tissue and smooth muscle cells: their action in smooth muscle cells in vitro. Endocrinology. 130:1716–27.PubMedGoogle Scholar
  76. 76.
    Helmke BM, et al. (2011) HMGA proteins regulate the expression of FGF2 in uterine fibroids. Mol Hum. Reprod. 17:135–42.PubMedCrossRefGoogle Scholar
  77. 77.
    Lemmon MA, Schlessinger J. (2010) Cell signaling by receptor tyrosine kinases. Cell. 141:1117–34.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Yu L, et al. (2008) Differential expression of receptor tyrosine kinases (RTKs) and IGF-I pathway activation in human uterine leiomyomas. Mol. Med. 14:264–75.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Swartz CD, Afshari CA, Yu L, Hall KE, Dixon D. (2005) Estrogen-induced changes in IGF-I, Myb family and MAP kinase pathway genes in human uterine leiomyoma and normal uterine smooth muscle cell lines. Mol. Hum. Reprod. 11:441–50.PubMedCrossRefGoogle Scholar
  80. 80.
    Kolch W. (2000) Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem. J. 351 Pt 2:289–305.CrossRefGoogle Scholar
  81. 81.
    Li E, Hristova K. (2006) Role of receptor tyrosine kinase transmembrane domains in cell signaling and human pathologies. Biochemistry. 45:6241–51.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Johnson GL, Lapadat R. (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 298:1911–2.PubMedCrossRefGoogle Scholar
  83. 83.
    Monje P, Hernandez-Losa J, Lyons RJ, Castellone MD, Gutkind JS. (2005) Regulation of the transcriptional activity of c-Fos by ERK. A novel role for the prolyl isomerase PIN1. J. Biol. Chem. 280:35081–4.PubMedCrossRefGoogle Scholar
  84. 84.
    Lessl M, et al. (1997) Comparative messenger ribonucleic acid analysis of immediate early genes and sex steroid receptors in human leiomyoma and healthy myometrium. J. Clin. Endocrinol. Metab. 82:2596–600.PubMedCrossRefGoogle Scholar
  85. 85.
    Gustavsson I, et al. (2000) Tissue differences but limited sex steroid responsiveness of c-fos and c-jun in human fibroids and myometrium. Mol. Hum. Reprod. 6:55–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Filardo EJ, Quinn JA, Bland KI, Frackelton AR, Jr. (2000) Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol. Endocrin. 14:1649–60.CrossRefGoogle Scholar
  87. 87.
    Migliaccio A, Pagano M, Auricchio F. (1993) Immediate and transient stimulation of protein tyrosine phosphorylation by estradiol in MCF-7 cells. Oncogene. 8:2183–91.PubMedGoogle Scholar
  88. 88.
    Wong CW, McNally C, Nickbarg E, Komm BS, Cheskis BJ. (2002) Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade. Proc. Natl. Acad. Sci. U. S. A. 99:14783–8.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Nethrapalli IS, et al. (2001) Estradiol (E2) elicits SRC phosphorylation in the mouse neocortex: the initial event in E2 activation of the MAPK cascade? Endocrinology. 142:5145–8.PubMedCrossRefGoogle Scholar
  90. 90.
    Lopez GN, Turck CW, Schaufele F, Stallcup MR, Kushner PJ. (2001) Growth factors signal to steroid receptors through mitogen-activated protein kinase regulation of p160 coactivator activity. J. Biol. Chem. 276:22177–82.PubMedCrossRefGoogle Scholar
  91. 91.
    Cantley LC. (2002) The phosphoinositide 3-kinase pathway. Science. 296:1655–7.PubMedCrossRefGoogle Scholar
  92. 92.
    Karra L, et al. (2010) Changes related to phosphatidylinositol 3-kinase/Akt signaling in leiomyomas: possible involvement of glycogen synthase kinase 3alpha and cyclin D2 in the pathophysiology. Fertil. Steril. 93:2646–51.PubMedCrossRefGoogle Scholar
  93. 93.
    Jeong YJ, et al. (2010) 17beta-estradiol induces up-regulation of PTEN and PPARgamma in leiomyoma cells, but not in normal cells. Int. J. Oncol. 36:921–7.PubMedGoogle Scholar
  94. 94.
    Crabtree JS, et al. (2009) Comparison of human and rat uterine leiomyomata: identification of a dysregulated mammalian target of rapamycin pathway. Cancer Res. 69:6171–8.PubMedCrossRefGoogle Scholar
  95. 95.
    Derynck R, Zhang YE. (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 425:577–84.PubMedCrossRefGoogle Scholar
  96. 96.
    Chegini N, Luo X, Ding L, Ripley D. (2003) The expression of Smads and transforming growth factor beta receptors in leiomyoma and myometrium and the effect of gonadotropin releasing hormone analogue therapy. Mol. Cell. Endocrinol. 209:9–16.PubMedCrossRefGoogle Scholar
  97. 97.
    Fayed YM, Tsibris JC, Langenberg PW, Robertson AL Jr. (1989) Human uterine leiomyoma cells: binding and growth responses to epidermal growth factor, platelet-derived growth factor, and insulin. Lab. Invest. 60:30–7.PubMedGoogle Scholar
  98. 98.
    Liang M, Wang H, Zhang Y, Lu S, Wang Z. (2006) Expression and functional analysis of platelet-derived growth factor in uterine leiomyomata. Cancer Biol. Ther. 5:28–33.PubMedCrossRefGoogle Scholar
  99. 99.
    Ren Y, et al. (2011) Different effects of epidermal growth factor on smooth muscle cells derived from human myometrium and from leiomyoma. Fertil. Steril. 96:1015–20.PubMedCrossRefGoogle Scholar
  100. 100.
    Dixon D, He H, Haseman JK. (2000) Immunohistochemical localization of growth factors and their receptors in uterine leiomyomas and matched myometrium. Environ. Health Perspect. 108 Suppl 5:795–802.PubMedCrossRefGoogle Scholar
  101. 101.
    Brown LF, Detmar M, Tognazzi K, Abu-Jawdeh G, Iruela-Arispe ML. (1997) Uterine smooth muscle cells express functional receptors (flt-1 and KDR) for vascular permeability factor/vascular endothelial growth factor. Lab. Invest. 76:245–55.PubMedGoogle Scholar
  102. 102.
    Sanci M, et al. (2011) Immunolocalization of VEGF, VEGF receptors, EGF-R and Ki-67 in leiomyoma, cellular leiomyoma and leiomyosarcoma. Acta Histochem. 113:317–25.PubMedCrossRefGoogle Scholar
  103. 103.
    Gentry CC, et al. (2001) Quantification of vascular endothelial growth factor-A in leiomyomas and adjacent myometrium. Clin. Sci. (Lond). 101:691–5.PubMedCrossRefGoogle Scholar
  104. 104.
    Hassan MH, et al. (2008) Memy I: a novel murine model for uterine leiomyoma using adenovirus-enhanced human fibroid explants in severe combined immune deficiency mice. Am. J. Obstet. Gynecol. 199: 156.e151–8.CrossRefGoogle Scholar
  105. 105.
    Xu Q, et al. (2006) Progesterone receptor modulator CDB-2914 down-regulates vascular endothelial growth factor, adrenomedullin and their receptors and modulates progesterone receptor content in cultured human uterine leiomyoma cells. Hum. Reprod. 21:2408–16.PubMedCrossRefGoogle Scholar
  106. 106.
    Wolanska M, Bankowska-Guszczyn E, Jaworski S. (2008) [Fibroblast growth factor gene expression in uterine leiomyomas]. Ginekol. Pol. 79:555–9.PubMedGoogle Scholar
  107. 107.
    Wolanska M, Bankowski E. (2006) Fibroblast growth factors (FGF) in human myometrium and uterine leiomyomas in various stages of tumour growth. Biochimie. 88:141–6.PubMedCrossRefGoogle Scholar
  108. 108.
    Anania CA, Stewart EA, Quade BJ, Hill JA, Nowak RA. (1997) Expression of the fibroblast growth factor receptor in women with leiomyomas and abnormal uterine bleeding. Mol. Hum. Reprod. 3:685–91.PubMedCrossRefGoogle Scholar
  109. 109.
    Ikushima H, Miyazono K. (2010) TGFbeta signalling: a complex web in cancer progression. Nat. Rev. Cancer. 10:415–24.PubMedCrossRefGoogle Scholar
  110. 110.
    Elliott RL, Blobe GC. (2005) Role of transforming growth factor Beta in human cancer. J. Clin. Oncol. 23:2078–93.PubMedCrossRefGoogle Scholar
  111. 111.
    Blobe GC, Schiemann WP, Lodish HF. (2000) Role of transforming growth factor beta in human disease. N. Eng. J. Med. 342:1350–8.CrossRefGoogle Scholar
  112. 112.
    Lee BS, Nowak RA. (2001) Human leiomyoma smooth muscle cells show increased expression of transforming growth factor-beta 3 (TGF beta 3) and altered responses to the antiproliferative effects of TGF beta. J. Clin. Endocrinol. Metab 86:913–20.PubMedGoogle Scholar
  113. 113.
    Arici A, Sozen I. (2000) Transforming growth factor-beta3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation. Fertil. Steril. 73:1006–11.PubMedCrossRefGoogle Scholar
  114. 114.
    Salama SA, Diaz-Arrastia CR, Kilic GS, Kamel MW. (2012) 2-Methoxyestradiol causes functional repression of transforming growth factor beta3 signaling by ameliorating Smad and non-Smad signaling pathways in immortalized uterine fibroid cells. Fertil. Steril. 98:178–84.PubMedCrossRefGoogle Scholar
  115. 115.
    Tal R, Segars JH. (2013) The role of angiogenic factors in fibroid pathogenesis: potential implications for future therapy. Hum. Reprod. Update. 20:194–216.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Di Lieto A, et al. (2003) Effects of gonadotropin-releasing hormone agonists on uterine volume and vasculature and on the immunohistochemical expression of basic fibroblast growth factor (bFGF) in uterine leiomyomas. Int. J. Gynecol. Pathol. 22:353–8.PubMedCrossRefGoogle Scholar
  117. 117.
    Borahay MA, et al. (2014) Simvastatin potently induces calcium-dependent apoptosis of human leiomyoma cells. J. Biol. Chem. 289:35075–86.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Sefton EC, et al. (2013) MK-2206, an AKT inhibitor, promotes caspase-independent cell death and inhibits leiomyoma growth. Endocrinology. 154:4046–57.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Ruffolo RR, inventor; Wyeth, assignee. Use of an mTOR inhibitor in treatment of uterine leiomyoma. United States patent US 7,528,145. 2009 May 5.Google Scholar
  120. 120.
    De Falco M, et al. (2006) Preoperative treatment of uterine leiomyomas: clinical findings and expression of transforming growth factor-beta3 and connective tissue growth factor. J. Soc. Gynecol. Investig. 13:297–303.PubMedCrossRefGoogle Scholar
  121. 121.
    Logan CY, Nusse R. (2004) The Wnt signaling pathway in development and disease. Annu. Rev. Cell. Dev. Biol. 20:781–810.PubMedCrossRefGoogle Scholar
  122. 122.
    Mangioni S, et al. (2005) Overexpression of the Wnt5b gene in leiomyoma cells: implications for a role of the Wnt signaling pathway in the uterine benign tumor. J. Clin. Endocrinol. Metab. 90:5349–55.PubMedCrossRefGoogle Scholar
  123. 123.
    Makinen N, et al. (2011) MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Science. 334:252–5.PubMedCrossRefGoogle Scholar
  124. 124.
    Markowski DN, et al. (2012) MED12 mutations in uterine fibroids—their relationship to cytogenetic subgroups. Int. J. Cancer. 131:1528–36.PubMedCrossRefGoogle Scholar
  125. 125.
    Tanwar PS, et al. (2009) Constitutive activation of Beta-catenin in uterine stroma and smooth muscle leads to the development of mesenchymal tumors in mice. Biol. Reprod. 81:545–52.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Ono M, et al. (2013) Paracrine activation of WNT/beta-catenin pathway in uterine leiomyoma stem cells promotes tumor growth. Proc. Natl. Acad. Sci. U. S. A. 110:17053–8.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Rhinn M, Dolle P. (2012) Retinoic acid signalling during development. Development. 139:843–58.PubMedCrossRefGoogle Scholar
  128. 128.
    Niederreither K, Dolle P. (2008) Retinoic acid in development: towards an integrated view. Nat. Rev. Genet. 9:541–53.PubMedCrossRefGoogle Scholar
  129. 129.
    Boettger-Tong H, Shipley G, Hsu CJ, Stancel GM. (1997) Cultured human uterine smooth muscle cells are retinoid responsive. Proc. Soc. Exp. Biol. Med. 215:59–65.PubMedCrossRefGoogle Scholar
  130. 130.
    Zaitseva M, Vollenhoven BJ, Rogers PA. (2007) Retinoic acid pathway genes show significantly altered expression in uterine fibroids when compared with normal myometrium. Mol. Hum. Reprod. 13:577–85.PubMedCrossRefGoogle Scholar
  131. 131.
    Zaitseva M, Vollenhoven BJ, Rogers PA. (2008) Retinoids regulate genes involved in retinoic acid synthesis and transport in human myometrial and fibroid smooth muscle cells. Hum. Reprod. 23:1076–86.PubMedCrossRefGoogle Scholar
  132. 132.
    Catherino WH, Malik M. (2007) Uterine leiomyomas express a molecular pattern that lowers retinoic acid exposure. Fertil. Steril. 87:1388–98.PubMedCrossRefGoogle Scholar
  133. 133.
    Tsibris JC, et al. (1999) Human uterine leiomyomata express higher levels of peroxisome proliferator-activated receptor gamma, retinoid X receptor alpha, and all-trans retinoic acid than myometrium. Cancer Res. 59:5737–44.PubMedGoogle Scholar
  134. 134.
    Lattuada D, et al. (2007) Accumulation of retinoid X receptor-alpha in uterine leiomyomas is associated with a delayed ligand-dependent proteasome-mediated degradation and an alteration of its transcriptional activity. Mol. Endocrinol. 21:602–12.PubMedCrossRefGoogle Scholar
  135. 135.
    Gamage SD, et al. (2000) Efficacy of LGD1069 (Targretin), a retinoid X receptor-selective ligand, for treatment of uterine leiomyoma. J. Pharmacol. Exp. Ther. 295:677–81.PubMedGoogle Scholar
  136. 136.
    Holick MF. (1996) Vitamin D and bone health. J. Nutr. 126:1159S–64S.PubMedCrossRefGoogle Scholar
  137. 137.
    Deeb KK, Trump DL, Johnson CS. (2007) Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat. Rev. Cancer. 7:684–700.PubMedCrossRefGoogle Scholar
  138. 138.
    Sabry M, Al-Hendy A. (2012) Innovative oral treatments of uterine leiomyoma. Obstet. Gynecol. Int. 2012:943635.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Sabry M, et al. (2013) Serum vitamin D3 level inversely correlates with uterine fibroid volume in different ethnic groups: a cross-sectional observational study. Int. J. Womens Health. 5:93–100.PubMedPubMedCentralGoogle Scholar
  140. 140.
    Baird DD, Hill MC, Schectman JM, Hollis BW. (2013) Vitamin d and the risk of uterine fibroids. Epidemiology. 24:447–53.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Paffoni A, et al. (2013) Vitamin D status in women with uterine leiomyomas. J. Clin. Endocrinol. Metab. 98:E1374–8.PubMedCrossRefGoogle Scholar
  142. 142.
    Catherino WH, Eltoukhi HM, Al-Hendy A. (2013) Racial and ethnic differences in the pathogenesis and clinical manifestations of uterine leiomyoma. Semin. Reprod. Med. 31:370–9.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Halder SK, Osteen KG, Al-Hendy A. (2013) 1,25-dihydroxyvitamin d3 reduces extracellular matrix-associated protein expression in human uterine fibroid cells. Biol. Reprod. 89:150.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Blauer M, Rovio PH, Ylikomi T, Heinonen PK. (2009) Vitamin D inhibits myometrial and leiomyoma cell proliferation in vitro. Fertil. Steril. 91:1919–25.PubMedCrossRefGoogle Scholar
  145. 145.
    Halder SK, Sharan C, Al-Hendy A. (2012) 1,25-dihydroxyvitamin D3 treatment shrinks uterine leiomyoma tumors in the Eker rat model. Biol. Reprod. 86:116.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Sharan C, et al. (2011) Vitamin D inhibits proliferation of human uterine leiomyoma cells via catechol-O-methyltransferase. Fertil. Steril. 95:247–53.PubMedCrossRefGoogle Scholar
  147. 147.
    Halder SK, Goodwin JS, Al-Hendy A. (2011) 1,25-Dihydroxyvitamin D3 reduces TGF-beta3-induced fibrosis-related gene expression in human uterine leiomyoma cells. J. Clin. Endocrinol. Metab. 96:E754–62.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Halder SK, Osteen KG, Al-Hendy A. (2013) Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and −9 in human uterine fibroid cells. Hum. Reprod. 28:2407–16.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Catherino WH, et al. (2004) Reduced dermatopontin expression is a molecular link between uterine leiomyomas and keloids. Genes Chromosomes Cancer. 40:204–17.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Leppert PC, et al. (2004) Comparative ultrastructure of collagen fibrils in uterine leiomyomas and normal myometrium. Fertil. Steril. 82 Suppl 3:1182–7.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Fujita M. (1985) Histological and biochemical studies of collagen in human uterine leiomyomas [in Japanese]. Hokkaido Igaku Zasshi. 60:602–15.PubMedGoogle Scholar
  152. 152.
    Malik M, Norian J, McCarthy-Keith D, Britten J, Catherino WH. (2010) Why leiomyomas are called fibroids: the central role of extracellular matrix in symptomatic women. Semin. Reprod. Med. 28:169–79.PubMedCrossRefGoogle Scholar
  153. 153.
    Norian JM, et al. Characterization of tissue biomechanics and mechanical signaling in uterine leiomyoma. Matrix Biol. 31:57–65.PubMedCrossRefGoogle Scholar
  154. 154.
    Wang N, Tytell JD, Ingber DE. (2009) Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nat. Rev. Mol. Cell. Biol. 10:75–82.PubMedCrossRefGoogle Scholar
  155. 155.
    Rogers R, et al. (2008) Mechanical homeostasis is altered in uterine leiomyoma. Am. J. Obstet. Gynecol. 198: 474.e1–11.CrossRefGoogle Scholar
  156. 156.
    Islam MS, et al. (2014) Tranilast, an orally active antiallergic compound, inhibits extracellular matrix production in human uterine leiomyoma and myometrial cells. Fertil. Steril. 102:597–606.PubMedCrossRefGoogle Scholar
  157. 157.
    Levy G, et al. (2014) Liarozole inhibits transforming growth factor-beta3-mediated extracellular matrix formation in human three-dimensional leiomyoma cultures. Fertil. Steril. 102:272–81.e2.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Evans RM, Barish GD, Wang YX. (2004) PPARs and the complex journey to obesity. Nat. Med. 10:355–61.PubMedCrossRefGoogle Scholar
  159. 159.
    Ahmadian M, et al. (2013) PPARgamma signaling and metabolism: the good, the bad and the future. Nat. Med. 19:557–66.PubMedCrossRefGoogle Scholar
  160. 160.
    Houston KD, et al. (2003) Inhibition of proliferation and estrogen receptor signaling by peroxisome proliferator-activated receptor gamma ligands in uterine leiomyoma. Cancer Res. 63:1221–7.PubMedGoogle Scholar
  161. 161.
    Nam DH, et al. (2007) Growth inhibition and apoptosis induced in human leiomyoma cells by treatment with the PPAR gamma ligand ciglitizone. Mol. Hum. Reprod. 13:829–36.PubMedCrossRefGoogle Scholar
  162. 162.
    Young SL, Al-Hendy A, Copland JA. (2004) Potential nonhormonal therapeutics for medical treatment of leiomyomas. Semin. Reprod. Med. 22:121–30.PubMedCrossRefGoogle Scholar
  163. 163.
    McCarty MF. (2004) Targeting multiple signaling pathways as a strategy for managing prostate cancer: multifocal signal modulation therapy. Integr. Cancer Ther. 3:349–80.PubMedCrossRefGoogle Scholar

Copyright information

© The Author(s) 2015

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  1. 1.Department of Obstetrics and GynecologyUniversity of Texas Medical BranchGalvestonUSA
  2. 2.Department of Biochemistry and Molecular BiologyUniversity of Texas Health Science CenterHoustonUSA
  3. 3.Department of Obstetrics and Gynecology, Medical College of GeorgiaGeorgia Regents UniversityAugustaUSA

Personalised recommendations