http://cancerres.aacrjournals.org/content/early/2012/04/17/0008-5472.CAN-11-2619.abstract
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 (HT) 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 HT use and colorectal cancer
risk differs by the molecular pathological 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 HT use, cancer risk, and specific tumor biomarkers in 581 incident colon and rectal cancer
cases that occurred during 26 years of follow-up among 105520
postmenopausal women. We found a difference between HT use and
colorectal cancer
risk according to CDKN1A expression (p-value for heterogeneity=0.01).
Current HT 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 HT use and cancer
risk according to MSI, CDKN1B, or TP53 status. Together, our molecular
epidemiology findings suggest a preventive effect of HT against
colorectal carcinogenesis which depends, in part, on loss of
cyclin-dependent kinase inhibitor CDKN1A.
