title: Postmenopausal hormone therapy is associated with a reduced risk of colorectal cancer lacking CDKN1A expression.
abstract: Experimental studies have shown that estrogen- or progesterone-activated signaling leads to growth inhibition effects on colon cancer cells through the upregulation of several cell-cycle regulators. However, epidemiologic studies evaluating hormone therapy use and colorectal cancer risk by the status of cell-cycle regulators are lacking. In this study, we used data from the prospective Nurses' Health Study to evaluate whether the association between hormone therapy use and colorectal cancer risk differs by the molecular pathologic status of microsatellite instability (MSI) and expression of cell-cycle-related tumor biomarkers, including CDKN1A (p21, CIP1), CDKN1B (p27, KIP1), and TP53 (p53) by immunohistochemistry. Duplication Cox regression analysis was used to determine an association between hormone therapy use, cancer risk, and specific tumor biomarkers in 581 incident colon and rectal cancer cases that occurred during 26 years of follow-up among 105,520 postmenopausal women. We found a difference between hormone therapy use and colorectal cancer risk according to CDKN1A expression (P(heterogeneity) = 0.01). Current hormone therapy use was associated with a reduced risk for CDKN1A-nonexpressed [multivariate relative risk (RR), 0.61; 95% confidence interval (CI), 0.46-0.82] but not for CDKN1A-expressed (RR, 1.32; 95% CI, 0.76-2.31) tumors. The lower risk for CDKN1A-nonexpressed but not for CDKN1A-expressed cancers was also present among current users of estrogen-alone therapy. We found no significant difference in the relations between hormone therapy use and cancer risk according to MSI, CDKN1B, or TP53 status. Together, our molecular pathological epidemiology findings suggest a preventive effect of hormone therapy against colorectal carcinogenesis that depends, in part, on loss of cyclin-dependent kinase inhibitor CDKN1A.
authors.affiliation: Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA. jhlin@rics.bwh.harvard.edu
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Lin
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.forename: Aya
authors.initials: A
authors.lastname: Kuchiba
authors.forename: Kaori
authors.initials: K
authors.lastname: Shima
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.forename: Gregory
authors.initials: G
authors.lastname: Kirkner
authors.forename: Shumin M
authors.initials: SM
authors.lastname: Zhang
authors.forename: Joann E
authors.initials: JE
authors.lastname: Manson
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000517:prevention & control; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015914:Estrogen Replacement Therapy; D005260:Female; D006801:Humans; D053842:Microsatellite Instability; D008875:Middle Aged; D009726:Nurses; D011446:Prospective Studies; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27