Abstract
BACKGROUNDGenetics of estrogen synthesis and breast cancer risk has been elusive. The 1245A→C missense-encoding polymorphism in HSD3B1, which is common in White populations, is functionally adrenal permissive and increases synthesis of the aromatase substrate androstenedione. We hypothesized that homozygous inheritance of the adrenal-permissive HSD3B1(1245C) is associated with postmenopausal estrogen receptor–positive (ER-positive) breast cancer.METHODSA prospective study of postmenopausal ER-driven breast cancer was done for determination of HSD3B1 and circulating steroids. Validation was performed in 2 other cohorts. Adrenal-permissive genotype frequency was compared between postmenopausal ER-positive breast cancer, the general population, and postmenopausal ER-negative breast cancer.RESULTSProspective and validation studies had 157 and 538 patients, respectively, for the primary analysis of genotype frequency by ER status in White female breast cancer patients who were postmenopausal at diagnosis. The adrenal-permissive genotype frequency in postmenopausal White women with estrogen-driven breast cancer in the prospective cohort was 17.5% (21/120) compared with 5.4% (2/37) for ER-negative breast cancer (P = 0.108) and 9.6% (429/4451) in the general population (P = 0.0077). Adrenal-permissive genotype frequency for estrogen-driven postmenopausal breast cancer was validated using Cambridge and The Cancer Genome Atlas data sets: 14.4% (56/389) compared with 6.0% (9/149) for ER-negative breast cancer (P = 0.007) and the general population (P = 0.005). Circulating androstenedione concentration was higher with the adrenal-permissive genotype (P = 0.03).CONCLUSIONAdrenal-permissive genotype is associated with estrogen-driven postmenopausal breast cancer. These findings link genetic inheritance of endogenous estrogen exposure to estrogen-driven breast cancer.FUNDINGNational Cancer Institute, NIH (R01CA236780, R01CA172382, and P30-CA008748); and Prostate Cancer Foundation Challenge Award.
Highlights
Estrogen exposure increases the risk of estrogen receptor–driven (ER-driven) breast cancer
Twenty-one of 120 (17.5%) White women with ER-positive breast cancer had the adrenal-permissive genotype, which was significantly higher than the general population (P = 0.0077; Table 1)
Because the hypothesis being tested was specific to postmenopausal breast cancer, enrollment in our prospective single-institution study was limited to patients who were postmenopausal at diagnosis, but we examined the adrenal-permissive genotype frequencies of premenopausal patients with breast cancer in the validation cohorts
Summary
Estrogen exposure increases the risk of estrogen receptor–driven (ER-driven) breast cancer. Mutations in DNA repair pathway components and certain tumor-suppressive genes, inherited genetics of estrogen synthesis has not been causally and reproducibly linked to endogenous estrogen exposure that in turn drives increased risk of breast cancer [4]. This may be due to inadequate power for such studies that interrogate multiple loci, the need to account for genetic variability in geography and race, other variations in hormonal physiology that might dilute such an effect, a combination of these factors, or the absence of such a link. We hypothesized that homozygous inheritance of the adrenal-permissive HSD3B1(1245C) is associated with postmenopausal estrogen receptor–positive (ER-positive) breast cancer
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