title: Molecular pathways: Estrogen pathway in colorectal cancer.
abstract: Worldwide, colorectal cancer has a higher incidence rate in men than in women, suggesting a protective role for sex hormones in the development of the disease. Preclinical data support a role for estrogen and its receptors in the initiation and progression of colorectal cancer and establishes that protective effects of estrogen are exerted through ERβ. Hormone replacement therapy (HRT) in postmenopausal women as well as consumption of soy reduces the incidence of colorectal cancer. In the Women's Health Initiative trial, use of HRT in postmenopausal women reduced the risk of colon cancer by 56% [95% confidence interval (CI), 0.38-0.81; P = 0.003]. A recent meta-analysis showed that in women, consumption of soy reduced the risk of colon cancer by 21% (95% CI, 0.03-0.35; P = 0.026). In this review, using the preclinical data, we translate the findings in the clinical trials and observational studies to define the role of estrogen in the prevention of colorectal cancer. We hypothesize that sometime during the tumorigenesis process ERβ expression in colonocytes is lost and the estrogen ligand, HRT, or soy products, exerts its effects through preventing this loss. Thus, in the adenoma-to-carcinoma continuum, timing of HRT is a significant determinant of the observed benefit from this intervention. We further argue that the protective effects of estrogen are limited to certain molecular subtypes. Successful development of estrogen modulators for prevention of colorectal cancer depends on identification of susceptible colorectal cancer population(s). Thus, research to better understand the estrogen pathway is fundamental for clinical delivery of these agents.
authors: Authors' Affiliations: USC Norris Comprehensive Cancer Center, Los Angeles; and Azusa Pacific University, Azusa, California.
authors: Afsaneh
authors: A
authors: Barzi
authors: Annika Medea
authors: AM
authors: Lenz
authors: Melissa J
authors: MJ
authors: Labonte
authors: Heinz-Josef
authors: HJ
authors: Lenz
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011374:Progesterone / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D057170:Translational Research, Biomedical
chemical_list: D004967:Estrogens; D011960:Receptors, Estrogen; D011374:Progesterone
references: Clin Cancer Res. 2009 Oct 15;15(20):6391-7
references: 19789331
references: Cancer Causes Control. 2012 Oct;23(10):1599-605
references: 22855257
references: Cancer Res. 2000 Jan 15;60(2):245-8
references: 10667568
references: Cancer Res. 1996 Oct 1;56(19):4516-21
references: 8813150
references: Hum Reprod. 2007 Jun;22(6):1769-77
references: 17347166
references: Eur J Cancer Prev. 2000 Apr;9(2):99-104
references: 10830576
references: Cancer Causes Control. 1999 Oct;10(5):467-73
references: 10530618
references: Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8517-21
references: 8078914
references: J Endocrinol. 1999 Dec;163(3):379-83
references: 10588810
references: Mol Cell Biol. 2007 Jan;27(2):466-80
references: 17074804
references: J Biol Chem. 2004 Sep 24;279(39):40255-8
references: 15304487
references: J Natl Cancer Inst. 1995 Apr 5;87(7):517-23
references: 7707438
references: Menopause. 2008 May-Jun;15(3):442-53
references: 18202593
references: Trends Biochem Sci. 2004 Jan;29(1):18-24
references: 14729328
references: J Natl Cancer Inst. 2010 Jul 21;102(14):1012-22
references: 20587792
references: Biochem Biophys Res Commun. 1999 Aug 2;261(2):521-7
references: 10425218
references: Endocr Rev. 1997 Aug;18(4):502-19
references: 9267762
references: Nutr Cancer. 2011;63(1):139-50
references: 21161820
references: BMC Cancer. 2011 Jun 03;11:219
references: 21639915
references: J Nutr. 2004 Jan;134(1):179-82
references: 14704314
references: Nat Rev Cancer. 2003 Aug;3(8):601-14
references: 12894248
references: J Biol Chem. 2002 Jul 5;277(27):24353-60
references: 11986316
references: Physiol Rev. 2001 Oct;81(4):1535-65
references: 11581496
references: Oncol Rep. 2005 Jul;14(1):17-21
references: 15944762
references: Trends Endocrinol Metab. 2002 Dec;13(10):422-7
references: 12431838
references: Cancer Causes Control. 2009 May;20(4):409-16
references: 18998219
references: PLoS One. 2010 Jul 27;5(7):e11791
references: 20668547
references: Eur J Epidemiol. 2012 Jun;27(6):439-52
references: 22644109
references: Int J Cancer. 2011 Apr 15;128(8):1881-9
references: 20533550
references: N Engl J Med. 2004 Mar 4;350(10):991-1004
references: 14999111
references: Mol Carcinog. 2011 May;50(5):359-69
references: 21480389
references: Cancer Epidemiol Biomarkers Prev. 2009 Nov;18(11):2835-41
references: 19843681
references: Biochem Biophys Res Commun. 1999 Sep 16;263(1):257-62
references: 10486286
references: Mol Endocrinol. 2011 Jun;25(6):969-79
references: 21493669
references: Cancer Causes Control. 2003 Dec;14(10):979-84
references: 14750537
references: J Med Food. 2005 Winter;8(4):431-8
references: 16379552
references: Endocrinology. 1973 Jan;92(1):125-34
references: 4681918
references: Int J Cancer. 2008 Jul 15;123(2):303-311
references: 18464259
references: J Clin Endocrinol Metab. 1999 Jun;84(6):2080-5
references: 10372714
references: Endocrinology. 1999 Dec;140(12):5566-78
references: 10579320
references: Int J Cancer. 2012 May 15;130(10):2387-96
references: 21671473
references: Biochem Biophys Res Commun. 1997 Jun 9;235(1):99-102
references: 9196043
references: Endocr Relat Cancer. 2005 Jul;12 Suppl 1:S75-84
references: 16113101
references: J Soc Gynecol Investig. 2000 Jan-Feb;7(1 Suppl):S3-7
references: 10732320
references: Science. 1997 Sep 5;277(5331):1508-10
references: 9278514
references: Biochem Biophys Res Commun. 1986 Feb 26;135(1):98-104
references: 3954781
references: BMC Cancer. 2012 Jul 03;12:276
references: 22759347
references: Steroids. 2005 May-Jun;70(5-7):418-26
references: 15862825
references: J Womens Health (Larchmt). 2005 May;14(4):299-305
references: 15916502
references: Breast Cancer Res Treat. 2010 Apr;120(3):557-65
references: 19434490
references: Diagn Mol Pathol. 2008 Dec;17(4):231-6
references: 19034156
references: Cancer Epidemiol Biomarkers Prev. 2000 Aug;9(8):781-6
references: 10952094
references: Cancer Epidemiol Biomarkers Prev. 2010 Jan;19(1):148-58
references: 20056634
references: J Clin Epidemiol. 2007 Jul;60(7):686-95
references: 17573984
references: Eur J Cancer. 2003 Jun;39(9):1251-8
references: 12763213
references: Mol Endocrinol. 2010 Sep;24(9):1703-14
references: 20363876
references: Mol Cell Endocrinol. 2001 Jan 22;171(1-2):53-60
references: 11165011
references: Cancer Res. 2007 Aug 1;67(15):7534-9
references: 17671225
references: J Clin Oncol. 2006 Dec 20;24(36):5680-6
references: 17179103
references: Endocrinology. 2011 Jun;152(6):2256-65
references: 21505049
references: Carcinogenesis. 2011 Nov;32(11):1675-83
references: 21856997
references: Cancer Res. 2001 Mar 15;61(6):2547-51
references: 11289129
references: Steroids. 2008 Oct;73(9-10):885-8
references: 18329060
references: Cancer Res. 2009 Aug 1;69(15):6100-6
references: 19602591
references: Eur J Gastroenterol Hepatol. 2010 May;22(5):614-9
references: 20173645
references: Biochem Biophys Res Commun. 2000 Apr 13;270(2):425-31
references: 10753641
references: Oncol Res. 1999;11(6):255-64
references: 10691027
references: Menopause. 2009 May-Jun;16(3):458-65
references: 19182698