Pigment epithelium-derived factor: clinical significance in estrogen-dependent tissues and its potential in cancer therapy

Document Type: Review Article


1 Departamento de Ginecología y Obstetricia, Hospital Mayor Mederi, Bogotá DC, Colombia

2 Facultad de Ciencias Naturales y Matemáticas, Universidad del Rosario, Bogotá DC, Colombia


Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the family of non-inhibitory serpins. The broad spectrum of PEDF biological activity is evident when considering its effects in promoting cell survival and proliferation, as well as its antiangiogenic, antitumor, and anti-metastatic properties. Although the structural domains of the PEDF gene that mediate such diverse effects and their mechanisms of action have not been completely elucidated, there is a large body of evidence describing their diverse range of activities; this evidence combined with the regulation of PEDF expression by sex steroids and their receptors have led to the idea that PEDF is not only a diagnostic and prognostic marker for certain diseases such as cancer, but is also a potential therapeutic target. In this manner, this paper aims to generally review the regulation of PEDF expression and PEDF interactions, as well as the findings that relate PEDF to the role of estrogens and estrogen receptors. In addition, this manuscript will review major advances toward potential therapeutic applications of PEDF.


1. Tombran-Tink J, Chader GG, Johnson LV. PEDF: a pigment epithelium-derived factor with potent neuronal differentiative activity. Exp Eye Res 1991; 53:411– 414.

2. Bilak MM, Corse AM, Bilak SR, Lehar M, Tombran-Tink J, Kuncl RW. Pigment epithelium-derived factor (PEDF) protects motor neurons from chronic glutamate-mediated neurodegeneration. J Neuropathol Exp Neurol 1999; 58:719-728.

3. Kuncl RW, Bilak MM, Bilak SR, Corse AM, Royal W, Becerra SP. Pigment epithelium-derived factor is elevated in CSF of patients with amyotrophic lateral sclerosis. J Neurochem 2002; 81:178-184.

4. Alberdi E, Hyde CC, Becerra SP. Pigment epithelium-derived factor (PEDF) binds to glycosaminoglycans: analysis of the binding site. Biochemistry 1998; 37:10643-10652.

5. Sawant S, Aparicio S, Tink AR, Lara N, Barnstable CJ, Tombran-Tink J. Regulation of factors controlling angiogenesis in liver development: a role for PEDF in the formation and maintenance of normal vasculature. Biochem Biophys Res Commun 2004; 325:408-413.

6. Palmieri D, Watson JM, Rinehart CA. Age-related expression of PEDF/EPC-1 in human endometrial stromal fibroblasts: implications for interactive senescence. Exp Cell Res 1999; 247:142-147.

7. Tombran-Tink J, Barnstable CJ. Therapeutic prospects for PEDF: more than a promising angiogenesis inhibitor. Trends Mol Med 2003; 9:244-250.

8. Chuderland D, Ben-Ami I, Friedler S, Hasky N, Ninio-Many L, Goldberg K, et al. Hormonal regulation of pigment epithelium-derived factor (PEDF) expression in the endometrium. Mol Cell Endocrinol 2014a; 390:85-92.

9. Chuderland D, Ben-Ami I, Kaplan-Kraicer R, Grossman H, Komsky A, Satchi-Fainaro R, et al. Hormonal regulation of pigment epithelium-derived factor (PEDF) in granulosa cells. Mol Hum Reprod 2013a; 19:72-81.

10. Doll JA, Stellmach VM, Bouck NP, Bergh AR, Lee C, Abramson LP, et al. Pigment epithelium-derived factor regulates the vasculature and mass of the prostate and pancreas. Nat Med 2003; 9:774-780.

11. Quan GM, Ojaimi J, Li Y, Kartsogiannis V, Zhou H, Choong PF. Localization of pigment epithelium-derived factor in growing mouse bone. Calcif Tissue Int 2005; 76:146-153.

12. Guan M, Yam HF, Su B, Chan KP, Pang CP, Liu WW, et al. Loss of pigment epithelium derived factor expression in glioma progression. J Clin Pathol 2003; 56:277-282.

12. Maik-Rachline G, Shaltiel S, Seger R. Extracellular phosphorylation converts pigment epithelium-derived factor from a neurotrophic to an antiangiogenic factor. Blood 2005; 105:670-678.

13. Tsuru M, Arima N, Toyozumi Y, Kato S. Pigment epithelium-derived factor as a new diagnostic marker for melanocytic tumors. Kurume Med J 2005; 52:81-87.

14. Hoshina D, Abe R, Yamagishi SI, Shimizu H. The role of PEDF in tumor growth and metastasis. Curr Mol Med 2010; 10:292-295.

15. Jan R, Huang M, Lewis-Wambi J. Loss of pigment epithelium-derived factor: a novel mechanism for the development of endocrine resistance in breast cancer. Breast Cancer Res 2012; 14:R146.

16. Chen L, Fan R, Huang X, Xu H, Zhang X. Decreased concentrations of pigment epithelium-derived factor in peritoneal fluid of patients with endometriosis. Fertil Steril 2011; 95:1798-1800.

17. Chen L, Fan R, Huang X, Xu H, Zhang X. Reduced levels of serum pigment epithelium-derived factor in women with endometriosis. Reprod Sci 2012; 19:64-69.

18. Sun Y, Che X, Zhu L, Zhao M, Fu G, Huang X, et al. Pigment epithelium derived factor inhibits the growth of human endometrial implants in nude mice and of ovarian endometriotic stromal cells in vitro.  PLoS One 2012; 7:e45223.

19. Fu G, Che X, Sun Y, Huang X, Xu H, Zhou C, et al. Pigment epithelial-derived factor expression in endometriotic lesions in a rat model of endometriosis. Acta Histochem 2013; 115:301-307.

20. Yang S, Li Q, Zhong L, Song Y, Tian B, Cheng Q, et al. Serum pigment epithelium-derived factor is elevated in women with polycystic ovary syndrome and correlates with insulin resistance. J Clin Endocrinol Metab 2011; 96:831-836.

21. Cheng Q, Xia W, Yang S, Ye P, Mei M, Song Y, et al. Association of serum pigment epithelium-derived factor with high-sensitivity C-reactive protein in women with polycystic ovary syndrome. J Endocrinol Invest 2013a; 36:632-635.

22. Gattu AK, Birkenfeld AL, Jornayvaz F, Dziura J, Li F, Crawford SE, et al. Insulin resistance is associated with elevated serum pigment epithelium-derived factor (PEDF) levels in morbidly obese patients. Acta Diabetol 2012; 49:S161-169.

23. Moreno-Navarrete JM, Touskova V, Sabater M, Mraz M, Drapalova J, Ortega F, et al. Liver, but not adipose tissue PEDF gene expression is associated with insulin resistance. Int J Obes (Lond) 2013; 37:1230-1237.

24. Choi KM, Hwang SY, Hong HC, Yang SJ, Choi HY, Yoo HJ, et al. C1q/TNF-related protein-3 (CTRP-3) and pigment epithelium-derived factor (PEDF) concentrations in patients with type 2 diabetes and metabolic syndrome. Diabetes 2012; 61:2932-2936.

25. Jenkins AJ, Fu D, Azar M, Stoner JA, Kaufman DG, Zhang S, et al. Clinical correlates of serum pigment epithelium-derived factor in type 2 diabetes patients. J Diabetes Complications 2014; 28:353-359.

26. Zhou D, Cheng SQ, Ji HF, Wang JS, Xu HT, Zhang GQ, et al. Evaluation of protein pigment epithelium-derived factor (PEDF) and microvessel density (MVD) as prognostic indicators in breast cancer. J Cancer Res Clin Oncol 2010; 136(11):1719-1727.

26. Zhu XF, Zou HD. PEDF in diabetic retinopathy: a protective effect of oxidative stress. J Biomed Biotechnol 2012; 2012:580687.

27. Wang H, Feng L, Hu JW, Xie CL, Wang F. Characterization of the vitreous proteome in proliferative diabetic retinopathy. Proteome Sci 2012; 10:15.

28. Wang F, Ma X, Zhou M, Pan X, Ni J, Gao M, et al. Serum pigment epithelium-derived factor levels are independently correlated with the presence of coronary artery disease. Cardiovasc Diabetol 2013; 12:56.

29. Yamagishi S, Matsui T. Pigment epithelium-derived factor (PEDF) and cardiometabolic disorders. Curr Pharm Des 2014; 20:2377-2386.

30. Xu X, Zhang SS, Barnstable CJ, Tombran-Tink J. Molecular phylogeny of the antiangiogenic and neurotrophic serpin, pigment epithelium derived factor in vertebrates. BMC Genomics 2006; 7:248.

31. Phillips NJ, Ziegler MR, Radford DM, Fair KL, Steinbrueck T, Xynos FP, et al. Allelic deletion on chromosome 17p13.3 in early ovarian cancer. Cancer Res 1996; 56:606-611.

32. Cheung LW, Au SC, Cheung AN, Ngan HY, Tombran-Tink J, Auersperg N, et al. Pigment epithelium-derived factor is estrogen sensitive and inhibits the growth of human ovarian cancer and ovarian surface epithelial cells. Endocrinology 2006; 147:4179-4191.

33. Houenou LJ, D'Costa AP, Li L, Turgeon VL, Enyadike C, Alberdi E, et al. Pigment epithelium-derived factor promotes the survival and differentiation of developing spinal motor neurons. J Comp Neurol 1999; 412:506-514.

34. Murray AR, Ma JX. PEDF as a treatment for cervical cancer. Cancer Biol Ther 2010; 9:975-977.

35. Ek ET, Dass CR, Contreras KG, Choong PF. Inhibition of orthotopic osteosarcoma growth and metastasis by multitargeted antitumour activities of pigment epithelium-derived factor. Clin Exp Metastasis 2007a; 24:93-106.

36. Dass CR, Ek ET, Choong PF. PEDF as an emerging therapeutic candidate for osteosarcoma. Curr Cancer Drug Targets 2008; 8:683-690.

37. Lattier JM, Yang H, Crawford S, Grossniklaus HE. Host pigment epithelium-derived factor (PEDF) prevents progression of liver metastasis in a mouse model of uveal melanoma. Clin Exp Metastasis 2013; 30:969-976.

38. Simonovic M, Gettins PG, Volz K. Crystal structure of human PEDF, a potent anti-angiogenic and neurite growth-promoting factor. Proc Natl Acad Sci USA 2001; 98:11131-11135.

39. Filleur S, Nelius T, de Riese W, Kennedy RC. Characterization of PEDF: a multi-functional serpin family protein. J Cell Biochem 2009; 106:769-775.

40. Broadhead ML, Becerra SP, Choong PF, Dass CR. The applied biochemistry of PEDF and implications for tissue homeostasis. Growth Factors 2010; 28:280-285.

41. Kawaguchi T, Yamagishi SI, Sata M. Structure-Function Relationships of PEDF. Curr Mol Med 2010; 10:302-311.

42. Anguissola S, McCormack WJ, Morrin MA, Higgins WJ, Fox DM, Worrall DM. Pigment epithelium-derived factor (PEDF) interacts with transportin SR2, and active nuclear import is facilitated by a novel nuclear localization motif.  PLoS One 2011; 6:e26234.

43. Pignolo RJ, Francis MK, Rotenberg MO, Cristofalo VJ. Putative role for EPC-1/PEDF in the G0 growth arrest of human diploid fibroblasts. J Cell Physiol 2003; 195:12-20.

44. Tombran-Tink J, Aparicio S, Xu X, Tink AR, Lara N, Sawant S, et al. PEDF and the serpins: phylogeny, sequence conservation, and functional domains. J Struct Biol 2005; 151:130-150.

45. Tombran-Tink J, Shivaram SM, Chader GJ, Johnson LV, Bok D. Expression, secretion, and age-related downregulation of pigment epithelium-derived factor, a serpin with neurotrophic activity. J Neurosci 1995; 15:4992-5003.

46. Tombran-Tink J, Lara N, Aparicio SE, Potluri P, Gee S, Ma JX, et al. Retinoic acid and dexamethasone regulate the expression of PEDF in retinal and endothelial cells. Exp Eye Res 2004; 78:945-955.

47. Irving JA, Shushanov SS, Pike RN, Popova EY, Bromme D, Coetzer TH, et al. Inhibitory activity of a heterochromatin-associated serpin (MENT) against papain-like cysteine proteinases affects chromatin structure and blocks cell proliferation. J Biol Chem 2002; 277:13192-13201.

48. Kojima T, Nakahama K, Yamamoto K, Uematsu H, Morita I. Age- and cell cycle-dependent changes in EPC-1/PEDF promoter activity in human diploid fibroblast-like (HDF) cells. Mol Cell Biochem 2006; 293:63-69.

49. Oei SL, Babich VS, Kazakov VI, Usmanova NM, Kropov AV, Tomilin NV. Clusters of regulatory signals for RNA polymerase 2 transcription associated with Alu family repeats and CpG islands in human promoters. Genomics 2004; 83:873-882.

50. Sasaki Y, Naishiro Y, Oshima Y, Imai K, Nakamura Y, Tokino T. Identification of pigment epithelium-derived factor as a direct target of the p53 family member genes. Oncogene 2005; 24:5131513-5131516.

51. Broadhead ML, Dass CR, Choong PF. Cancer cell apoptotic pathways mediated by PEDF: prospects for therapy. Trends Mol Med 2009; 15:461-467.

52. Ho TC, Chen SL, Shih SC, Chang SJ, Yang SL, Hsieh JW, et al. Pigment epithelium-derived factor (PEDF) promotes tumor cell death by inducing macrophage membrane tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). J Biol Chem 2011; 286:35943-35954.

53. Bonofiglio D, Aquila S, Catalano S, Gabriele S, Belmonte M, Middea E, et al. Peroxisome proliferator-activated receptor-gamma activates p53 gene promoter binding to the nuclear factor-kappaB sequence in human MCF7 breast cancer cells. Mol Endocrinol 2006; 20:3083-3092.

54. Gaetano C, Colussi C, Capogrossi MC. PEDF, PPAR-gamma, p53: deadly circuits arise when worlds collide. Cardiovasc Res 2007; 76:195-196.

55. Becerra SP, Notario V. The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential. Nat Rev Cancer 2013; 13:258-271.

56. Yasui N, Mori T, Morito D, Matsushita O, Kourai H, Nagata K, et al. Dual-site recognition of different extracellular matrix components by anti-angiogenic/neurotrophic serpin, PEDF. Biochemistry 2003; 42:3160-3167.

57. Notari L, Arakaki N, Mueller D, Meier S, Amaral J, Becerra SP. Pigment epithelium-derived factor binds to cell-surface F(1)-ATP synthase. FEBS J 2010; 277:2192-2205.

58. Anne SL, Govek EE, Ayrault O, Kim JH, Zhu X, Murphy DA, et al. WNT3 inhibits cerebellar granule neuron progenitor proliferation and medulloblastoma formation via MAPK activation. PLoS One 2013; 8:e81769.

59. Matsui T, Higashimoto Y, Yamagishi S. Laminin receptor mediates anti-inflammatory and anti-thrombogenic effects of pigment epithelium-derived factor in myeloma cells. Biochem Biophys Res Commun 2014; 443:847-851.

60. Subramanian P, Locatelli-Hoops S, Kenealey J, DesJardin J, Notari L, Becerra SP. Pigment epithelium-derived factor (PEDF) prevents retinal cell death via PEDF Receptor (PEDF-R): identification of a functional ligand binding site. J Biol Chem 2013; 288:23928-23942.

61. Notari L, Baladron V, Aroca-Aguilar JD, Balko N, Heredia R, Meyer C, et al. Identification of a lipase-linked cell membrane receptor for pigment epithelium-derived factor. J Biol Chem 2006; 281:38022-38037.

62. Mukherjee PK, Marcheselli VL, Barreiro S, Hu J, Bok D, Bazan NG. Neurotrophins enhance retinal pigment epithelial cell survival through neuroprotectin D1 signalling. Proc Natl Acad Sci USA 2007; 104:13152-13157.

63. Taniwaki T, Hirashima N, Becerra SP, Chader GJ, Etcheberrigaray R, Schwartz JP. Pigment epithelium-derived factor protects cultured cerebellar granule cells against glutamate-induced neurotoxicity. J Neurochem 1997; 68:26-32.

64. Volpert OV, Zaichuk T, Zhou W, Reiher F, Ferguson TA, Stuart PM, et al. Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor. Nat Med 2002; 8:349-357.

65. Bouck N. PEDF: anti-angiogenic guardian of ocular function. Trends Mol Med 2002; 8:330-334.

66. Bernard A, Gao-Li J, Franco CA, Bouceba T, Huet A, Li Z. Laminin receptor involvement in the anti-angiogenic activity of pigment epithelium-derived factor. J Biol Chem 2009; 284:10480-10490.

67. Li JK, Liang HL, Li Z, Gu CH, Yi DH, Pei JM. Pigment epithelium-derived factor promotes Fas-induced cardiomyocyte apoptosis via its receptor phospholipase A2. Life Sci 2014; 99:18-23.

68. Chung C, Doll JA, Gattu AK, Shugrue C, Cornwell M, Fitchev P, et al. Anti-angiogenic pigment epithelium-derived factor regulates hepatocyte triglyceride content through adipose triglyceride lipase (ATGL). J Hepatol 2008; 48:471-478.

69. Chavan SS, Hudson LK, Li JH, Ochani M, Harris Y, Patel NB, et al. Identification of pigment epithelium-derived factor as an adipocyte-derived inflammatory factor. Mol Med 2012; 18:1161-1168.

70. Ramírez-Castillejo C, Sánchez-Sánchez F, Andreu-Agulló C, Ferrón SR, Aroca-Aguilar JD, Sánchez P, et al. Pigment epithelium-derived factor is a niche signal for neural stem cell renewal. Nat Neurosci 2006; 9:331-339.

71. Yamagishi S, Nakamura K, Takenaka K, Matsui T, Jinnouchi Y, Imaizumi T. Pigment epithelium-derived factor (PEDF) promotes growth of pericytes through autocrine production of platelet-derived growth factor-B. Microvasc Res 2005; 69:128-1234.

72. Yabe T, Kanemitsu K, Sanagi T, Schwartz JP, Yamada H. Pigment epithelium-derived factor induces pro-survival genes through cyclic AMP-responsive element binding protein and nuclear factor kappa B activation in rat cultured cerebellar granule cells: Implication for its neuroprotective effect. Neuroscience 2005; 133:691-700.

73. Becerra SP, Sagasti A, Spinella P, Notario V. Pigment epithelium-derived factor behaves like a noninhibitory serpin. Neurotrophic activity does not require the serpin reactive loop. J Biol Chem 1995; 270:25992-25999.

74. Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 1999; 285:245-248.

75. Yabe T, Wilson D, Schwartz JP. NFkappaB activation is required for the neuroprotective effects of pigment epithelium-derived factor (PEDF) on cerebellar granule neurons. J Biol Chem 2001; 276:43313-43319.

76. Cai J, Jiang WG, Grant MB, Boulton M. Pigment epithelium-derived factor inhibits angiogenesis via regulated intracellular proteolysis of vascular endothelial growth factor receptor 1. J Biol Chem 2006; 281:3604–3613.

77. Ablonczy Z, Prakasam A, Fant J, Fauq A, Crosson C, Sambamurti K. Pigment epithelium-derived factor maintains retinal pigment epithelium function by inhibiting vascular endothelial growth factor-R2 signaling through gamma-secretase. J Biol Chem 2009; 284:30177-30186.

78. Cai J, Chen Z, Ruan Q, Han S, Liu L, Qi X, et al. γ-Secretase and presenilin mediate cleavage and phosphorylation of vascular endothelial growth factor receptor-1. J Biol Chem 2011; 286:42514-42523.

79. Konson A, Pradeep S, D’Acunto CW, Seger R. Pigment epithelium-derived factor and its phosphomimetic mutant induce JNK-dependent apoptosis and p38-mediated migration arrest. J Biol Chem 2011; 286:3540-3551.

80. Ho TC, Chen SL, Yang YC, Lo TH, Hsieh JW, Cheng HC, et al. Cytosolic phospholipase A2-{alpha} is an early apoptotic activator in PEDF-induced endothelial cell apoptosis. Am J Physiol Cell Physiol 2009; 296:C273-284.

81. Pollina EA, Legesse-Miller A, Haley EM, Goodpaster T, Randolph-Habecker J, Coller HA. Regulating the angiogenic balance in tissues. Cell Cycle 2008; 7:2056-2070.

82. Chen J, Ye L, Zhang L, Jian WG. The molecular impact of pigment epithelium-derived factor, PEDF, on lung cancer cells and the clinical significance. Int J Oncol 2009; 35:159-166.

83. Fan W, Crawford R, Xiao Y. The ratio of VEGF/PEDF expression in bone marrow mesenchymal stem cells regulates neovascularization. Differentiation 2011; 81:181-191.

84. Patil CK, Mian S, Campisi J. The thorny path linking cellular senescence to organismal aging. Mech Ageing Dev 2005; 126:1040-1045.

85. Chuaire-Noack L, Sánchez-Corredor MC, Ramírez-Clavijo SR. The dual role of senescence in tumorigenesis. Int J Morphol 2010a; 28:37-50.

86. Chuaire-Noack L, Rondón-Lagos S, Sánchez-Corredor M, Ibáñez-Pinilla M, Ramírez-Clavijo S. Beta-galactosidase activity as a marker of senescence in primary cultures of the ovarian surface epithelium. Invest Clin 2010b; 51:351-367.

87. Pignolo RJ, Cristofalo VJ, Rotenberg MO. Senescent WI-38 cells fail to express EPC-1, a gene induced in young cells upon entry into the G0 state. J Biol Chem 1993; 268: 8949-8957.

88. Fernández-Barral A, Orgaz JL, Baquero P,                Ali Z, Moreno A, Tiana M, et al. Regulatory and functional connection of microphthalmia-associated transcription factor and anti-metastatic pigment epithelium derived factor in melanoma. Neoplasia 2014; 16:529-542.

89. Cao Y, Yang T, Gu C, Yi D. Pigment epithelium-derived factor delays cellular senescence of human mesenchymal stem cells in vitro by reducing oxidative stress. Cell Biol Int 2013; 34:305-313.

90. Chuaire-Noack L, Sánchez-Corredor MC, Ramírez-Clavijo S. P53 and its role in the ovarian surface epithelium. Invest Clin 2008; 49:561-593.

91. Steinle JJ, Sharma S, Chin VC. Normal aging involves altered expression of growth factors in the rat choroid. J Gerontol A Biol Sci Med Sci 2008; 63A:135-140.

92. Francis MK, Appel S, Meyer C, Balin SJ, Balin AK, Cristofalo VJ. Loss of EPC-1/PEDF expression during skin aging In vivo. J Invest Dermatol 2004; 122:1096-1105.

93. Guan M, Pang CP, Yam HF, Cheung KF, Liu WW, Lu Y. Inhibition of glioma invasion by overexpression of pigment epithelium-derived factor. Cancer Gene Ther 2004; 11:325-332.

94. Hase R, Miyamoto M, Uehara H, Kadoya M, Ebihara Y, Murakami Y, et al. Pigment epithelium-derived factor gene therapy inhibits human pancreatic cancer in mice. Clin Cancer Res 2005; 11:8737-8344.

95. Streck CJ, Zhang Y, Zhou J, Ng C, Nathwani AC, Davidoff AM. Adeno-associated virus vector-mediated delivery of pigment epithelium-derived factor restricts neuroblastoma angiogenesis and growth. J Pediatr Surg 2005; 40:236-243.

96. Guan M, Jiang H, Xu C, Xu R, Chen Z, Lu Y. Adenovirus-mediated PEDF expression inhibits prostate cancer cell growth and results in augmented expression of PAI-2. Cancer Biol Ther 2007; 6:419-425.

97. Uehara H, Miyamoto M, Kato K, Ebihara Y, Kaneko H, Hashimoto H, et al. Expression of pigment epithelium-derived factor decreases liver metastasis and correlates with favorable prognosis for patients with ductal pancreatic adenocarcinoma. Cancer Res 2004; 64:3533-3537.

98. Abramson LP, Browne M, Stellmach V, Doll J, Cornwell M, Reynolds M, et al. Pigment epithelium-derived factor targets endothelial and epithelial cells in Wilms' tumour. J Pediatr Surg 2006; 41:1351-1356.

99. Ji D, Li M, Zhan T, Yao Y, Shen J, Tian H, et al. Prognostic role of serum AZGP1, PEDF and PRDX2 in colorectal cancer patients. Carcinogenesis 2013; 34:1265-1272.

100. Zhang L, Chen J, Ke Y, Mansel RE, Jiang WG. Expression of pigment epithelial derived factor is reduced in non-small cell lung cancer and is linked to clinical outcome. Int J Mol Med 2006; 17:937-944.

101. Caldon CE. Estrogen signaling and the DNA damage response in hormone dependent breast cancers. Front Oncol 2014; 4:106.

102. Dey P, Barros RP, Warner M, Ström A, Gustafsson JÅ. Insight into the mechanisms of action of estrogen receptor β in the breast, prostate, colon, and CNS. J Mol Endocrinol 2013; 51:T61-74.

103. Parvathaneni K, Grigsby JG, Betts BS, Tsin AT. Estrogen-induced retinal endothelial cell proliferation: Possible involvement of Pigment Epithelium-Derived Factor and Phosphoinositide 3-Kinase/Mitogen-Activated Protein Kinase pathways. J Ocul Pharmacol Ther 2013; 29:27-32.

104. Manolagas SC, O'Brien CA, Almeida M. The role of estrogen and androgen receptors in bone health and disease. Nat Rev Endocrinol 2013; 9:699-712.

105. Shao R, Cao S, Wang X, Feng Y, Billig H. The elusive and controversial roles of estrogen and progesterone receptors in human endometriosis. Am J Transl Res 2014; 6:104-113.

106. Grantham JP, Henneberg M. The estrogen hypothesis of obesity. PLoS One 2014; 9:e99776.

107. Paterni I, Granchi C, Katzenellenbogen JA, Minutolo F. Estrogen receptors alpha (ERα) and beta (ERβ): Subtype-selective ligands and clinical potential. Steroids 2014; 90:13-29.

108. Young NA, Friedman AK, Kaffenberger B, Rajaram MV, Birmingham DJ, Rovin BH, et al. Novel estrogen target gene ZAS3 is overexpressed in systemic lupus erythematosus. Mol Immunol 2013; 54:23-31.

109. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321-333.

110. Kumar R, Zakharov MN, Khan SH, Miki R, Jang H, Toraldo G, et al. The dynamic structure of the estrogen receptor. J Amino Acids 2011; 2011:812540.

111. Miller JH, Gates RE Jr, Ong DE, King LE Jr. A miniature molecular-sieving column assay for cytoplasmic vitamin A-binding proteins. Anal Biochem 1984; 139:104-114.

112. Kumar V, Green S, Stack G, Berry M, Jin JR, Chambon P. Functional domains of the human estrogen receptor. Cell 1987; 51:941-951.

113. Webb P, Nguyen P, Valentine C, Lopez GN, Kwok GR, McInerney E, et al. The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions. Mol Endocrinol 1999; 13:1672-1685.

114. Saville B, Wormke M, Wang F, Nguyen T, Enmark E, Kuiper G, et al. Ligand-, cell-, and estrogen receptor subtype (alpha/beta)-dependent activation at GC-rich (Sp1) promoter elements. J Biol Chem 2000; 275:5379-5387.

115. Xu J, Wu RC, O'Malley BW. Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family. Nat Rev Cancer 2009; 9:615-630.

116. Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 1995; 270:1491-1494.

117. Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn ME, Karas RH. Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha. Proc Natl Acad Sci USA 2004; 101:17126-17131.

118. Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev 2007; 87:905-931.

119. Knowlton AA, Korzick DH. Estrogen and the female heart. Mol Cell Endocrinol 2014; 389:31-39.

120. Vivar OI, Zhao X, Saunier EF, Griffin C, Mayba OS, Tagliaferri M, et al. Estrogen receptor beta binds to and regulates three distinct classes of target genes. J Biol Chem 2010; 285:22059-22066.

121. Paruthiyil S, Parmar H, Kerekatte V, Cunha GR, Firestone GL, Leitman DC. Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer Res 2004; 64:423-428.

122. Cvoro A, Tatomer D, Tee MK, Zogovic T, Harris HA, Leitman DC. Selective estrogen receptor-beta agonists repress transcription of proinflammatory genes. J Immunol 2008; 180:630-636.

123. Liu MM, Albanese C, Anderson CM, Hilty K, Webb P, Uht RM, et al. Opposing action of estrogen receptors alpha and beta on cyclin D1 gene expression. J Biol Chem 2002; 277:24353-24360.

124. Prossnitz ER, Barton M. The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol 2011; 7:715-726.

125. Prossnitz ER, Barton M. Estrogen biology: new insights into GPER function and clinical opportunities. Mol Cell Endocrinol 2014; 389:71-83.

126. Wang H, Jessup JA, Lin MS, Chagas C, Lindsey SH, Groban L. Activation of GPR30 attenuates diastolic dysfunction and left ventricle remodeling in oophorectomized mRen2. Lewis rats. Cardiovasc Res 2012; 94:96-104.

127. Tombran-Tink J, Mazuruk K, Rodriguez IR, Chung D, Linker T, Englander E, et al. Organization, evolutionary conservation, expression and unusual Alu density of the human gene for pigment epithelium-derived factor, a unique neurotrophic serpin. Mol Vis 1996; 2:11.

128. Leung KW, Cheung LW, Pon YL, Wong RN, Mak NK, Fan TP, et al. Ginsenoside Rb1 inhibits tube-like structure formation of endothelial cells by regulating pigment epithelium-derived factor through the oestrogen beta receptor. Br J Pharmacol 2007; 152:207-215.

129. Garvin S, Ollinger K, Dabrosin C. Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo. Cancer Lett 2006; 231:113-122.

130. Li C, Tang Y, Li F, Turner S, Li K, Zhou X, et al. 17beta-estradiol (betaE2) protects human retinal Müller cell against oxidative stress in vitro: evaluation of its effects on gene expression by cDNA microarray. Glia 2006; 53:392-400.

131. Mowa CN, Iwanaga T. Differential distribution of oestrogen receptor-alpha and -beta mRNAs in the female reproductive organ of rats as revealed by in situ hybridization. J Endocrinol 2000; 165:59-66.

132. Pelletier G, El-Alfy M. Immunocytochemical localization of estrogen receptors alpha and beta in the human reproductive organs. J Clin Endocrinol Metab 2000; 85:4835-4840.

133. Emmen JM, Couse JF, Elmore SA, Yates MM, Kissling GE, Korach KS. In vitro growth and ovulation of follicles from ovaries of estrogen receptor (ER){alpha} and ER{beta} null mice indicate a role for ER{beta} in follicular maturation. Endocrinology 2005; 146:2817-2826.

134. Lenie S, Smitz J. Estrogen receptor subtypes localization shifts in cultured mouse ovarian follicles. Histochem Cell Biol 2008; 129:827-840.

135. Brandenberger AW, Tee MK, Jaffe RB. Estrogen receptor alpha (ER-alpha) and beta (ER-beta) mRNAs in normal ovary, ovarian serous cystadenocarcinoma and ovarian cancer cell lines: down-regulation of ER-beta in neoplastic tissues. J Clin Endocrinol Metab 1998; 83:1025-1028.

136. Jarkovska K, Kupcova Skalnikova H, Halada P, Hrabakova R, Moos J, Rezabek K, et al. Development of ovarian hyperstimulation syndrome: interrogation of key proteins and biological processes in human follicular fluid of women undergoing in vitro fertilization. Mol Hum Reprod 2011; 17:679-692.

137. Twigt J, Steegers-Theunissen RP, Bezstarosti K, Demmers JA. Proteomic analysis of the microenvironment of developing oocytes. Proteomics 2012; 12:1463-1471.

138. Kampfer C, Saller S, Windschüttl S, Berg D, Berg U, Mayerhofer A. Pigment Epithelium Derived Factor (PEDF) and the human ovary: a role in the generation of ROS in granulosa cells. Life Sci 2014; 97:129-136.

139. Joham AE, Teede HJ, Hutchison SK, Stepto NK, Harrison CL, Strauss BJ, et al. Pigment epithelium-derived factor, insulin sensitivity, and adiposity in polycystic ovary syndrome: impact of exercise training. Obesity (Silver Spring) 2012; 20:2390-2396.

140. Lecke SB, Morsch D, Spritzer PM. Circulating levels and subcutaneous adipose tissue gene expression of pigment epithelium-derived factor in polycystic ovary syndrome and normal women: a case control study. Reprod Biol Endocrinol 2013; 11:77.

141. Chuderland D, Ben-Ami I, Bar-Joseph H, Shalgi R. Pigment epithelium derived factor (PEDF) in the reproductive system. Reproduction 2014b; 148:R53-61.

142. Humaidan P, Quartarolo J, Papanikolaou EG. Preventing ovarian hyperstimulation syndrome: guidance for the clinician. Fertil Steril 2010; 94:389-400.

143. Bates DO, Harper SJ. Regulation of vascular permeability by vascular endothelial growth factors. Vascul Pharmacol 2002; 39:225-237.

144. Chuderland D, Ben-Ami I, Kaplan-Kraicer R, Grossman H, Ron-El R, Shalgi R. The role of pigment epithelium-derived factor in the pathophysiology and treatment of ovarian hyperstimulation syndrome in mice. J Clin Endocrinol Metab 2013b; 98:E258-266.

145. Tsuchiya T, Nakahama KI, Asakawa Y, Maemura T, Tanaka M, Takeda S, et al. The reduction in pigment epithelium-derived factor is a sign of malignancy in ovarian cancer expressing low-level of vascular endothelial growth factor. Gynecol Endocrinol 2009; 25:104-109.

146. Rutherford T, Brown WD, Sapi E, Aschkenazi S, Muñoz A, Mor G. Absence of estrogen receptor-β expression in metastatic ovarian cancer. Obstet Gynecol 2000: 96: 417-421.

147. Chan KK, Wei N, Liu SS, Xiao-Yun L, Cheung AN, Ngan HY. Estrogen receptor subtypes in ovarian cancer. A clinical correlation. Obstet Gynecol 2008; 111:144-151.

148. Halon A, Nowak-Markwitz E, Maciejczyk A, Pudelko M, Gansukh T, Györffy B, et al. Loss of estrogen receptor beta expression correlates with shorter overall survival and lack of clinical response to chemotherapy in ovarian cancer patients. Anticancer Res 2011; 31:711-718.

149. Fujimoto J, Hirose R, Sakaguchi H, Tamaya T. Clinical significance of expression of estrogen receptor alpha and beta mRNAs in ovarian cancers. Oncology 2000; 58: 334-341.

150. Johns A, Freay AD, Fraser W, Korach KS, Rubanyi GM. Disruption of estrogen receptor gene prevents 17 beta estradiol-induced angiogenesis in transgenic mice. Endocrinology 1996; 137:4511-4513.

151. May K, Becker CM. Endometriosis and angiogenesis. Minerva Ginecol 2008; 60:245-254.

152. Weigelt B, Banerjee S. Molecular targets and targeted therapeutics in endometrial cancer. Curr Opin Oncol 2012; 24:554-563.

153. Torry DS, Leavenworth J, Chang M, Maheshwari V, Groesch K, Ball ER, et al. Angiogenesis in implantation. J Assist Reprod Genet 2007; 24:303-315.

154. Saji S, Jensen EV, Nilsson S, Rylander T, Warner M, Gustafsson JA. Estrogen receptors alpha and beta in the rodent mammary gland. Proc Natl Acad Sci USA 2000; 97:337-342.

155. Cheng G, Butler R, Warner M, Gustafsson JÅ, Wilczek B, Landgren BM. Effects of short-term estradiol and norethindrone acetate treatment on the breasts of normal postmenopausal women. Menopause 2013b; 20:496-503.

156. Förster C, Mäkela S, Wärri A, Kietz S, Becker D, Hultenby K, et al. Involvement of estrogen receptor beta in terminal differentiation of mammary gland epithelium. Proc Natl Acad Sci USA 2002; 99:15578-15583. Erratum in: Proc Natl Acad Sci USA 2006; 103:8298.

157. Lattrich C, Juhasz-Boess I, Ortmann O, Treeck O. Detection of an elevated HER2 expression in MCF-7 breast cancer cells overexpressing estrogen receptor beta1. Oncol Rep 2008; 19:811-817.

158. Fitzgerald DP, Subramanian P, Deshpande M, Graves C, Gordon I, Qian Y, et al. Opposing effects of pigment epithelium-derived factor on breast cancer cell versus neuronal survival: implication for brain metastasis and metastasis-induced brain damage. Cancer Res 2012; 72:144-153.

159. Broadhead ML, Choong PF, Dass CR. Efficacy of continuously administered PEDF-derived synthetic peptides against osteosarcoma growth and metastasis. J Biomed Biotechnol 2012; 2012:230298.

160. Rüegg C, Hasmim M, Lejeune FJ, Alghisi GC. Antiangiogenic peptides and proteins: from experimental tools to clinical drugs. Biochim Biophys Acta 2006; 1765:155-177.

161. Filleur S, Volz K, Nelius T, Mirochnik Y, Huang H, Zaichuk TA, et al. Two functional epitopes of pigment epithelial-derived factor block angiogenesis and induce differentiation in prostate cancer. Cancer Res 2005; 65:5144-5152.

162. Mirochnik Y, Aurora A, Schulze-Hoepfner FT, Deabes A, Shifrin V, Beckmann R, et al. Short pigment epithelial-derived factor-derived peptide inhibits angiogenesis and tumor growth. Clin Cancer Res 2009; 15:1655-1663.

163. Ek ET, Dass CR, Contreras KG, Choong PF. PEDF-derived synthetic peptides exhibit antitumor activity in an orthotopic model of human osteosarcoma. J Orthop Res 2007b; 25:1671-1680.

164. Demeule M, Regina A, Che C, Poirier J, Nguyen T, Gabathuler R, et al. Identification and design of peptides as a new drug delivery system for the brain. J Pharmacol Exp Ther 2008; 324:1064-1072.

165. Yang J, Chen S, Huang X, Han J, Wang Q, Shi D, et al. Growth suppression of cervical carcinoma by pigment epithelium-derived factor via anti-angiogenesis. Cancer Biol Ther 2010; 9:967-974.

166. Wu Q, He S, Wei X, Shao B, Luo S, Guo F, et al. Synergistic antitumor effect of rAAV-mediated PEDF with hyperthermia on solid tumor. Hum Gene Ther 2014; 25:811-823.

167. He SS, Wu QJ, Gong CY, Luo ST, Zhang S, Li M, et al. Enhanced efficacy of combination therapy with adeno‑associated virus-delivered pigment epithelium-derived factor and cisplatin in a mouse model of Lewis lung carcinoma. Mol Med Rep 2014; 9:2069-2076.

168. Chuderland D, Hasky N, Ben-Ami I, Kaplan-Kraicer R, Grossman H, Shalgi R. A physiological approach for treating endometriosis by recombinant pigment epithelium-derived factor (PEDF). Hum Reprod 2013c; 28:1626-1634.

169. Xu Z, Fang S, Zuo Y, Zhang Y, Cheng R, Wang Q, et al. Combination of pigment epithelium-derived factor with radiotherapy enhances the antitumor effects on nasopharyngeal carcinoma by downregulating vascular endothelial growth factor expression and angiogenesis. Cancer Sci 2011; 102:1789-1798.

170. Dass CR, Contreras KG, Dunstan DE, Choong PF. Chitosan microparticles encapsulating PEDF plasmid demonstrate efficacy in an orthotopic metastatic model of osteosarcoma. Biomaterials 2007; 28:3026-3033.

171. Ta HT, Dass CR, Larson I, Choong PF, Dunstan DE. A chitosan hydrogel delivery system for osteosarcoma gene therapy with pigment epithelium-derived factor combined with chemotherapy. Biomaterials 2009; 30:4815-4823.