Polymorphisms in genes involved in estrogen and progesterone metabolism and mammographic density changes in women randomized to postmenopausal hormone therapy: results from a pilot study.
BACKGROUND
Mammographic density is a strong independent risk factor for breast cancer, and can be modified by hormonal exposures. Identifying genetic variants that determine increases in mammographic density in hormone users may be important in understanding hormonal carcinogenesis of the breast.


METHODS
We obtained mammograms and DNA from 232 postmenopausal women aged 45 to 75 years who had participated in one of two randomized, double-blind clinical trials with estrogen therapy (104 women, taking 1 mg/day of micronized 17beta-estradiol, E2), combined estrogen and progestin therapy (34 women, taking 17beta-estradiol and 5 mg/day of medroxyprogesterone acetate for 12 days/month) or matching placebos (94 women). Mammographic percentage density (MPD) was measured on baseline and 12-month mammograms with a validated computer-assisted method. We evaluated polymorphisms in genes involved in estrogen metabolism (catechol-O-methyltransferase (COMT (Val158Met)), cytochrome P450 1B1 (CYP1B1 (Val432Leu)), UDP-glucuronosyltransferase 1A1 (UGT1A1 (<7/>or= 7 TA repeats))) and progesterone metabolism (aldo-keto reductase 1C4 (AKR1C4 (Leu311Val))) with changes in MPD.


RESULTS
The adjusted mean change in MPD was +4.6% in the estrogen therapy arm and +7.2% in the combined estrogen and progestin therapy arm, compared with +0.02% in the placebo arm (P = 0.0001). None of the genetic variants predicted mammographic density changes in women using estrogen therapy. Both the AKR1C4 and the CYP1B1 polymorphisms predicted mammographic density change in the combined estrogen and progestin therapy group (P < 0.05). In particular, the eight women carrying one or two low-activity AKR1C4 Val alleles showed a significantly greater increase in MPD (16.7% and 29.3%) than women homozygous for the Leu allele (4.0%).


CONCLUSIONS
Although based on small numbers, these findings suggest that the magnitude of the increase in mammographic density in women using combined estrogen and progestin therapy may be greater in those with genetically determined lower activity of enzymes that metabolize estrogen and progesterone.
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. sally.lord@ctc.usyd.edu.au
Sarah J
SJ
Lord
Wendy J
WJ
Mack
David
D
Van Den Berg
Malcolm C
MC
Pike
Sue A
SA
Ingles
Christopher A
CA
Haiman
Wei
W
Wang
Yuri R
YR
Parisky
Howard N
HN
Hodis
Giske
G
Ursin
D000368:Aged; D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000449:Aldehyde Reductase; D000074408:Aldo-Keto Reductases; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000201:enzymology / Q000209:etiology*; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D004311:Double-Blind Method; D004958:Estradiol / Q000378:metabolism; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D010865:Pilot Projects; D011110:Polymorphism, Genetic; D017698:Postmenopause; D011372:Progestins / Q000378:metabolism / Q000627:therapeutic use; D011859:Radiography; D012307:Risk Factors; D000099148:UGT1A1 Enzyme
D000429:Alcohol Oxidoreductases; D000449:Aldehyde Reductase; D000074408:Aldo-Keto Reductases; D001189:Aryl Hydrocarbon Hydroxylases; D002394:Catechol O-Methyltransferase; D065633:Cytochrome P-450 CYP1B1; D004958:Estradiol; D014453:Glucuronosyltransferase; D011372:Progestins; D000099148:UGT1A1 Enzyme; C585496:CYP1B1 protein, human