Methylation and miRNA effects of resveratrol on mammary tumors vs. normal tissue.
We reported that resveratrol decreased DNA methyltransferase (DNMT) 1 and 3b expression in vitro and demethylates tumor suppressor RASSF-1a in women at increased breast cancer risk. We investigated the effects of resveratrol on DNMT and miRNA expression in normal and tumor mammary tissue in a rodent model of estrogen dependent mammary carcinoma. Eighty-nine female ACI rats received estradiol plus: low dose (lo) resveratrol, high dose (hi) resveratrol, 5-aza-2-deoxycytidine (Aza), a known inhibitor of DNMTs, or control (no additional treatment). After 21 wk of treatment, animals were sacrificed and mammary glands harvested. Matched tumor/normal tissues were available from 36 rats. DMNT3b (but not DNMT1) differed in tumor vs. normal tissue after lo (P = .04) and hi (P = .007) resveratrol and Aza treatment. With hi resveratrol, DNMT3b decreased in tumor but increased normal tissue. Hi resveratrol increased miR21, -129, -204, and -489 >twofold in tumor and decreased the same miRs in normal tissue 10-50% compared to control. There was an inverse association between DNMT3b and miR129, -204, and -489 in normal and/or tumor tissue. Treatment with resveratrol differentially influences tumor vs. normal tissue DNMT3b and miRNA expression. This mechanism of action of resveratrol to influence mammary carcinogenesis warrants further investigation.
a Department of Surgery , University of Texas Health Science Center , Tyler , Texas , USA.
Wenyi
W
Qin
Ke
K
Zhang
Kaitlin
K
Clarke
Timothy
T
Weiland
Edward R
ER
Sauter
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D015536:Down-Regulation; D004967:Estrogens / Q000378:metabolism; D005260:Female; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011912:Rats, Inbred ACI; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D000097584:DNA Methyltransferase 3B
D001374:Azacitidine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000077209:Decitabine; D004967:Estrogens; D035683:MicroRNAs; D000077185:Resveratrol; D013267:Stilbenes; D000097584:DNA Methyltransferase 3B; C000619382:Dnmt1 protein, rat