Genetic variation in the progesterone receptor and metabolism pathways and hormone therapy in relation to breast cancer risk.
The relevance of progesterone to breast carcinogenesis is highlighted by evidence indicating that use of combined estrogen-progesterone therapy (EPT) is more strongly related to breast cancer risk than is use of unopposed estrogen therapy. However, few investigators have assessed how genetic variation in progesterone-related genes modifies the effect of EPT on risk. In an analysis combining data from 2 population-based case-control studies of postmenopausal breast cancer (1,296 cases and 1,055 controls) conducted in Washington State in 1997-1999 and 2000-2004, the authors evaluated how 51 single nucleotide polymorphisms in 7 progesterone-related genes (AKR1C1, AKR1C2, AKR1C3, CYP3A4, SRD5A1, SRD5A2, and PGR) influenced breast cancer risk. There was no appreciable association with breast cancer risk overall for any single nucleotide polymorphism. For rs2854482 in AKR1C2, carrying 1 or 2 A alleles was associated with a 2.0-fold increased breast cancer risk in EPT users (95% confidence interval: 1.0, 4.0) but not in never users (P(heterogeneity) = 0.03). For rs12387 in AKR1C3, the presence of 1 or 2 G alleles was associated with a 1.5-fold increased risk among EPT users (95% confidence interval: 1.1, 2.2) but not in never users (P(heterogeneity) = 0.02). Interpretation of these subgroup associations must await the results of similar studies conducted in other populations.
Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington 98109, USA. kreding@u.washington.edu
Kerryn W
KW
Reding
Christopher I
CI
Li
Noel S
NS
Weiss
Chu
C
Chen
Christopher S
CS
Carlson
David
D
Duggan
Kenneth E
KE
Thummel
Janet R
JR
Daling
Kathleen E
KE
Malone
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D000368:Aged; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001943:Breast Neoplasms / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D016001:Confidence Intervals; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics*; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics* / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D014861:Washington / Q000453:epidemiology; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
D015096:3-Hydroxysteroid Dehydrogenases; D000074425:Aldo-Keto Reductase Family 1 Member C3; D006911:Hydroxyprostaglandin Dehydrogenases; D006913:Hydroxysteroid Dehydrogenases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); C487341:AKR1C3 protein, human