Download PDF
Semin Reprod Med 2010; 28(3): 250-259
DOI: 10.1055/s-0030-1251482
Published in 2010 by Thieme Medical Publishers

Receptor Tyrosine Kinases and Their Hormonal Regulation in Uterine Leiomyoma

Linda Yu1 , Alicia B. Moore1 , Darlene Dixon1
  • 1Cellular and Molecular Pathology Branch (CMPB), National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina
Further Information

Publication History

Publication Date:
22 April 2010 (online)

    Permissions and Reprints

ABSTRACT

Uterine leiomyomas (fibroids, myomas) are benign tumors that develop from smooth muscle cells. Although the most common gynecologic tumor in premenopausal women, there is still little known of the etiology, the genetics and basic/molecular biology, or the influence of the environment on the development and growth of these tumors. The fact that fibroids occur during the reproductive years and regress after menopause indicates a growth dependent on ovarian hormones. Studies have supported a role of estrogen and progesterone in leiomyoma growth possibly through regulating growth factors and their signaling pathways. Activation of steroid hormone receptors can have a myriad of effects and include upregulation of growth factors and receptor tyrosine kinases (RTKs), which through downstream effector proteins such as mitogen-activated protein kinase p44/42, can mediate transcription, translation, and cell proliferation. Due to their hormonal dependency, fibroids may also be targeted by environmental chemicals whose biological effects are mediated through the estrogen and/or progesterone receptors. This review focuses on the role of growth factors and their receptors (RTKs) in uterine leiomyoma growth and their regulation by ovarian hormones. It also presents data on specific signaling pathways activated in uterine leiomyomas and the “cross talk” between the estrogen receptor α and RTK signaling pathways.

KEYWORDS

Receptor tyrosine kinases (RTKs) - hormonal regulation - uterus - leiomyoma - growth factors - fibroids

REFERENCES

  • 1 Li E, Hristova K. Role of receptor tyrosine kinase transmembrane domains in cell signaling and human pathologies.  Biochemistry. 2006;  45(20) 6241-6251
    CrossrefPubMedGoogle Scholar
  • 2 Bennasroune A, Gardin A, Aunis D, Crémel G, Hubert P. Tyrosine kinase receptors as attractive targets of cancer therapy.  Crit Rev Oncol Hematol. 2004;  50(1) 23-38
    CrossrefPubMedGoogle Scholar
  • 3 Ferrara N. VEGF and the quest for tumour angiogenesis factors.  Nat Rev Cancer. 2002;  2(10) 795-803
    CrossrefPubMedGoogle Scholar
  • 4 Yu L, Saile K, Swartz C D et al.. Differential expression of receptor tyrosine kinases (RTKs) and IGF-I pathway activation in human uterine leiomyomas.  Mol Med. 2008;  14(5–6) 264-275
    PubMedGoogle Scholar
  • 5 Wang J, Ohara N, Wang Z et al.. A novel selective progesterone receptor modulator asoprisnil (J867) down-regulates the expression of EGF, IGF-I, TGFbeta3 and their receptors in cultured uterine leiomyoma cells.  Hum Reprod. 2006;  21(7) 1869-1877
    CrossrefPubMedGoogle Scholar
  • 6 Flake G P, Andersen J, Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review.  Environ Health Perspect. 2003;  111(8) 1037-1054
    CrossrefPubMedGoogle Scholar
  • 7 Shushan A, Ben-Bassat H, Mishani E, Laufer N, Klein B Y, Rojansky N. Inhibition of leiomyoma cell proliferation in vitro by genistein and the protein tyrosine kinase inhibitor TKS050.  Fertil Steril. 2007;  87(1) 127-135
    CrossrefPubMedGoogle Scholar
  • 8 Mangrulkar R S, Ono M, Ishikawa M, Takashima S, Klagsbrun M, Nowak R A. Isolation and characterization of heparin-binding growth factors in human leiomyomas and normal myometrium.  Biol Reprod. 1995;  53(3) 636-646
    CrossrefPubMedGoogle Scholar
  • 9 Wolańska M, Bańkowski E. Fibroblast growth factors (FGF) in human myometrium and uterine leiomyomas in various stages of tumour growth.  Biochimie. 2006;  88(2) 141-146
    CrossrefPubMedGoogle Scholar
  • 10 Liang M, Wang H, Zhang Y, Lu S, Wang Z. Expression and functional analysis of platelet-derived growth factor in uterine leiomyomata.  Cancer Biol Ther. 2006;  5(1) 28-33
    CrossrefPubMedGoogle Scholar
  • 11 Van der Ven L T, Roholl P J, Gloudemans T et al.. Expression of insulin-like growth factors (IGFs), their receptors and IGF binding protein-3 in normal, benign and malignant smooth muscle tissues.  Br J Cancer. 1997;  75(11) 1631-1640
    CrossrefPubMedGoogle Scholar
  • 12 Crosier P S, Freeman S A, Orlic D, Bodine D M, Crosier K E. The Dtk receptor tyrosine kinase, which binds protein S, is expressed during hematopoiesis.  Exp Hematol. 1996;  24(2) 318-323
    PubMedGoogle Scholar
  • 13 Motoyoshi K. Function, molecular structure and gene expression of macrophage colony-stimulating factor [in Japanese].  Nippon Rinsho. 1992;  50(8) 1861-1866
    PubMedGoogle Scholar
  • 14 Pützer B M, Drosten M. The RET proto-oncogene: a potential target for molecular cancer therapy.  Trends Mol Med. 2004;  10(7) 351-357
    CrossrefPubMedGoogle Scholar
  • 15 Forrester W C. The Ror receptor tyrosine kinase family.  Cell Mol Life Sci. 2002;  59(1) 83-96
    CrossrefPubMedGoogle Scholar
  • 16 Hoch W. Molecular dissection of neuromuscular junction formation.  Trends Neurosci. 2003;  26(7) 335-337
    CrossrefPubMedGoogle Scholar
  • 17 Brantley-Sieders D M, Chen J. Eph receptor tyrosine kinases in angiogenesis: from development to disease.  Angiogenesis. 2004;  7(1) 17-28
    CrossrefPubMedGoogle Scholar
  • 18 Sun W S, Fujimoto J, Tamaya T. Clinical implications of coexpression of growth arrest-specific gene 6 and receptor tyrosine kinases Axl and Sky in human uterine leiomyoma.  Mol Hum Reprod. 2003;  9(11) 701-707
    CrossrefPubMedGoogle Scholar
  • 19 Schlessinger J, Lemmon M A. Nuclear signaling by receptor tyrosine kinases: the first robin of spring.  Cell. 2006;  127(1) 45-48
    CrossrefPubMedGoogle Scholar
  • 20 McKay M M, Morrison D K. Integrating signals from RTKs to ERK/MAPK.  Oncogene. 2007;  26(22) 3113-3121
    CrossrefPubMedGoogle Scholar
  • 21 Barbarisi A, Petillo O, Di Lieto A et al.. 17-beta estradiol elicits an autocrine leiomyoma cell proliferation: evidence for a stimulation of protein kinase-dependent pathway.  J Cell Physiol. 2001;  186(3) 414-424
    CrossrefPubMedGoogle Scholar
  • 22 Levin E R. Integration of the extranuclear and nuclear actions of estrogen.  Mol Endocrinol. 2005;  19(8) 1951-1959
    CrossrefPubMedGoogle Scholar
  • 23 Mesquita F S, Dyer S N, Heinrich D A et al.. Reactive oxygen species mediate mitogenic growth factor signaling pathways in human leiomyoma smooth muscle cells.  Biol Reprod. 2010;  82(2) 341-351
    CrossrefPubMedGoogle Scholar
  • 24 Orcy R B, Brum I, da Silva R S, Kucharski L C, Corleta H E, Capp E. Insulin receptor tyrosine kinase activity and substrate 1 (IRS-1) expression in human myometrium and leiomyoma.  Eur J Obstet Gynecol Reprod Biol. 2005;  123(1) 107-110
    CrossrefPubMedGoogle Scholar
  • 25 Cook J D, Walker C L. Treatment strategies for uterine leiomyoma: the role of hormonal modulation.  Semin Reprod Med. 2004;  22(2) 105-111
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Sozen I, Arici A. Interactions of cytokines, growth factors, and the extracellular matrix in the cellular biology of uterine leiomyomata.  Fertil Steril. 2002;  78(1) 1-12
    CrossrefPubMedGoogle Scholar
  • 27 Buttram Jr V C, Reiter R C. Uterine leiomyomata: etiology, symptomatology, and management.  Fertil Steril. 1981;  36(4) 433-445
    PubMedGoogle Scholar
  • 28 Dixon D, Flake G P, Moore A B et al.. Cell proliferation and apoptosis in human uterine leiomyomas and myometria.  Virchows Arch. 2002;  441(1) 53-62
    CrossrefPubMedGoogle Scholar
  • 29 Lannigan D A. Estrogen receptor phosphorylation.  Steroids. 2003;  68(1) 1-9
    CrossrefPubMedGoogle Scholar
  • 30 Bunone G, Briand P A, Miksicek R J, Picard D. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation.  EMBO J. 1996;  15(9) 2174-2183
    PubMedGoogle Scholar
  • 31 Hermon T L, Moore A B, Yu L, Kissling G E, Castora F J, Dixon D. Estrogen receptor alpha (ERalpha) phospho-serine-118 is highly expressed in human uterine leiomyomas compared to matched myometrium.  Virchows Arch. 2008;  453(6) 557-569
    CrossrefPubMedGoogle Scholar
  • 32 Shimomura Y, Matsuo H, Samoto T, Maruo T. Up-regulation by progesterone of proliferating cell nuclear antigen and epidermal growth factor expression in human uterine leiomyoma.  J Clin Endocrinol Metab. 1998;  83(6) 2192-2198
    CrossrefPubMedGoogle Scholar
  • 33 Yamada T, Nakago S, Kurachi O et al.. Progesterone down-regulates insulin-like growth factor-I expression in cultured human uterine leiomyoma cells.  Hum Reprod. 2004;  19(4) 815-821
    CrossrefPubMedGoogle Scholar
  • 34 Swartz C D, Afshari C A, Yu L, Hall K E, Dixon D. 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. 2005;  11(6) 441-450
    CrossrefPubMedGoogle Scholar
  • 35 Chegini N, Luo X, Ding L, Ripley D. 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. 2003;  209(1-2) 9-16
    CrossrefPubMedGoogle Scholar
  • 36 Kato S, Endoh H, Masuhiro Y et al.. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase.  Science. 1995;  270(5241) 1491-1494
    CrossrefPubMedGoogle Scholar
  • 37 Zhao Y, Zhang W, Wang S. The expression of estrogen receptor isoforms alpha, beta and insulin-like growth factor-I in uterine leiomyoma.  Gynecol Endocrinol. 2008;  24(10) 549-554
    CrossrefPubMedGoogle Scholar
  • 38 Hassan M H, Salama S A, Arafa H M, Hamada F M, Al-Hendy A. Adenovirus-mediated delivery of a dominant-negative estrogen receptor gene in uterine leiomyoma cells abrogates estrogen- and progesterone-regulated gene expression.  J Clin Endocrinol Metab. 2007;  92(10) 3949-3957
    CrossrefPubMedGoogle Scholar
  • 39 Dixon D, He H, Haseman J K. Immunohistochemical localization of growth factors and their receptors in uterine leiomyomas and matched myometrium.  Environ Health Perspect. 2000;  108(Suppl 5) 795-802
    CrossrefPubMedGoogle Scholar
  • 40 Di X, Yu L, Moore A B et al.. A low concentration of genistein induces estrogen receptor-alpha and insulin-like growth factor-I receptor interactions and proliferation in uterine leiomyoma cells.  Hum Reprod. 2008;  23(8) 1873-1883
    CrossrefPubMedGoogle Scholar
  • 41 van der Ven L T, Gloudemans T, Roholl P J et al.. Growth advantage of human leiomyoma cells compared to normal smooth-muscle cells due to enhanced sensitivity toward insulin-like growth factor I.  Int J Cancer. 1994;  59(3) 427-434
    CrossrefPubMedGoogle Scholar
  • 42 Murphy L J, Ghahary A. Uterine insulin-like growth factor-1: regulation of expression and its role in estrogen-induced uterine proliferation.  Endocr Rev. 1990;  11(3) 443-453
    CrossrefPubMedGoogle Scholar
  • 43 Adesanya O O, Zhou J, Bondy C A. Sex steroid regulation of insulin-like growth factor system gene expression and proliferation in primate myometrium.  J Clin Endocrinol Metab. 1996;  81(5) 1967-1974
    CrossrefPubMedGoogle Scholar
  • 44 Giudice L C, Irwin J C, Dsupin B A et al.. Insulin-like growth factor (IGF), IGF binding protein (IGFBP), and IGF receptor gene expression and IGFBP synthesis in human uterine leiomyomata.  Hum Reprod. 1993;  8(11) 1796-1806
    PubMedGoogle Scholar
  • 45 Newbold R R. Lessons learned from perinatal exposure to diethylstilbestrol.  Toxicol Appl Pharmacol. 2004;  199(2) 142-150
    CrossrefPubMedGoogle Scholar
  • 46 Newbold R R, Banks E P, Bullock B, Jefferson W N. Uterine adenocarcinoma in mice treated neonatally with genistein.  Cancer Res. 2001;  61(11) 4325-4328
    PubMedGoogle Scholar
  • 47 Hunter D S, Hodges L C, Eagon P K et al.. Influence of exogenous estrogen receptor ligands on uterine leiomyoma: evidence from an in vitro/in vivo animal model for uterine fibroids.  Environ Health Perspect. 2000;  108(suppl 5) 829-834
    CrossrefPubMedGoogle Scholar
  • 48 Adlercreutz H, Markkanen H, Watanabe S. Plasma concentrations of phyto-oestrogens in Japanese men.  Lancet. 1993;  342(8881) 1209-1210
    CrossrefPubMedGoogle Scholar
  • 49 Wang T T, Sathyamoorthy N, Phang J M. Molecular effects of genistein on estrogen receptor mediated pathways.  Carcinogenesis. 1996;  17(2) 271-275
    CrossrefPubMedGoogle Scholar

Darlene DixonD.V.M. Ph.D. 

Cellular and Molecular Pathology Branch, National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services

111 T.W. Alexander Drive, P.O. Box 12233, Bldg. 101/Rm C254A/MD C209, Research Triangle Park, NC 27709

Email: dixon@niehs.nih.gov

      >