Chemoprevention of Colorectal Neoplasia by Estrogen: Potential Role of Vitamin D Activity

Abstract

Postmenopausal hormone replacement therapy lowers colon cancer incidence. In humans, the mechanism is unknown, but animal models suggest that it may involve activation of the vitamin D receptor (VDR) pathway.The aims of our study were to determine whether estrogen intervention affects global gene expression in rectal mucosal biopsies and whether vitamin D-related genes are affected.Estradiol was given to raise serum estradiol to premenopausal levels in 10 postmenopausal women under close nutritional control. Primary end points were expression of VDR, CYP24A1, CYP27B1, and E-cadherin in rectal mucosa by reverse transcription-PCR and examining response to estradiol by genome-wide arrays. Responses in gene expression in rectal biopsies to estrogen were determined in each subject individually and compared with a human estrogen response gene array database and a custom array in vitro-generated database.Cluster analysis showed that subjects maintained their overall gene expression profile and that interindividual differences were greater than intraindividual differences after intervention. Eight of 10 subjects showed significant enrichment in estrogen-responsive genes. Gene array group analysis showed activation of the VDR pathway and down-regulation of inflammatory and immune signaling pathways. Reverse transcription-PCR analysis showed significant up-regulation of VDR and E-cadherin, a downstream target of vitamin D action.These data suggest that the chemopreventive action of hormone replacement therapy on colon neoplasia results, at least in part, from changes in vitamin D activity. Evaluation of gene arrays is useful in chemopreventive intervention studies in small groups of subjects.

Calcium and 1,25-dihydroxyvitamin D3 modulate genes of immune and inflammatory pathways in the human colon: a human crossover trial

“…Flexible sigmoidoscopies were performed after a 60-mL tap water enema between 0800 and 1000. Rectosigmoid mucosal biopsy specimens were taken w15 cm from the anal verge as described previously (15,16). Six biopsy specimens for gene expression analysis were taken, immediately frozen in liquid nitrogen, and stored at 2808C.…”

“…Our group has completed several studies of molecular events in rectosigmoid mucosal biopsy specimens that accompany administration of putative risk reduction agents such as estrogen and folic acid (15,16). The present study aimed to identify the effects of calcium and/or 1,25-dihydroxyvitamin D 3 [1,25 (OH) 2 D 3 ] supplementation on gene expression profiles of the human colorectal mucosa of subjects at moderate risk of CRC consuming a Western-style diet (WD).…”

Vitamin D and Colorectal Carcinogenesis

“…Additional data suggest that this action may, at least in part, be mediated through VDR signaling. RT-PCR results confirmed that estrogen administration increased mRNA expression of VDR as well as of a downstream target of vitamin D action, E-cadherin [140]. Besides HRT, high estrogen content of soy is implicated to be…”

“…When mice were fed a diet containing soy, the expression of the synthesizing vitamin D hydroxylase, CYP27B1, was enhanced, and that of the catabolic hydroxylase, CYP24A1, was decreased [50]. In a clinical pilot trial [140], postmenopausal women with a past history of rectal adenomas were given a daily dose of 17 β-estradiol for 1 month to reach premenopausal hormone levels. Rectal biopsies were obtained at the beginning and end of the trial.…”

Effects of changes in dietary habits on colorectal cancer incidence in twenty countries from four continents during the period 1971-2002

“…Risk factors include alcohol (11,12), red meat consumption (11,(13)(14)(15)(16), low vegetable and folate intake (17,18), smoking (19)(20)(21), sedentary lifestyle, overweight, obesity (22)(23)(24), diabetes (25) and short duration and poor quality of sleep (26); protective factors include fish consumption (14,15), hormone replacement therapy (27,28), oral contraceptive use (29), calcium intake (30), higher bone mass levels (31) and physical exercise (11,(32)(33)(34). The results from several epidemiological studies are inconsistent concerning the effects of dietary fiber intake (35)(36)(37)(38)(39).…”