Abstract
IntroductionEstrogen is important in the development of breast cancer, and its biological effects are mediated primarily through the two estrogen receptors alpha and beta. A point mutation in the estrogen receptor alpha gene, ESR1, referred to as A908G or K303R, was originally identified in breast hyperplasias and was reported to be hypersensitive to estrogen. We recently detected this mutation at a low frequency of 6% in invasive breast tumors of the Carolina Breast Cancer Study (CBCS).MethodsIn this report, we evaluated risk factors for invasive breast cancer classified according to the presence or absence of the ESR1 A908G mutation in the CBCS, a population-based case-control study of breast cancer among younger and older white and African-American women in North Carolina. Of the 653 breast tumors evaluated, 37 were ESR1 A908G mutation-positive and 616 were mutation-negative.ResultsESR1 A908G mutation-positive breast cancer was significantly associated with a first-degree family history of breast cancer (odds ratio [OR] = 2.69, 95% confidence interval [CI] = 1.15 to 6.28), whereas mutation-negative breast cancer was not. Comparison of the two case subgroups supported this finding (OR = 2.65, 95% CI = 1.15 to 6.09). There was also the suggestion that longer duration of oral contraceptive (OC) use (OR = 3.73, 95% CI = 1.16 to 12.03; Ptrend = 0.02 for use of more than 10 years) and recent use of OCs (OR = 3.63, 95% CI = 0.80 to 16.45; Ptrend = 0.10 for use within 10 years) were associated with ESR1 A908G mutation-positive breast cancer; however, ORs for comparison of the two case subgroups were not statistically significant. Hormone replacement therapy use was inversely correlated with mutation-negative breast cancer, but the effect on mutation-positive cancer was unclear due to the small number of postmenopausal cases whose tumors carried the mutation. Mutation-negative breast cancer was associated with several reproductive factors, including younger age at menarche (OR = 1.46, 95% CI = 1.09 to 1.94) and greater total estimated years of ovarian function (OR = 1.82, 95% CI = 1.21 to 2.74).ConclusionThese preliminary results suggest that OCs may interact with the ESR1 A908G mutant receptor to drive the development of some breast tumors.
Highlights
Estrogen is important in the development of breast cancer, and its biological effects are mediated primarily through the two estrogen receptors alpha and beta
ESR1 A908G mutation-positive breast cancer was significantly associated with a first-degree family history of breast cancer, whereas mutation-negative breast cancer was not
Mutation-negative breast cancer was associated with several reproductive factors, including younger age at menarche (OR = 1.46, 95% confidence intervals (CIs) = 1.09 to 1.94) and greater total estimated years of ovarian function (OR = 1.82, 95% CI = 1.21 to 2.74)
Summary
Estrogen is important in the development of breast cancer, and its biological effects are mediated primarily through the two estrogen receptors alpha and beta. A point mutation in the estrogen receptor alpha gene, ESR1, referred to as A908G or K303R, was originally identified in breast hyperplasias and was reported to be hypersensitive to estrogen. We recently detected this mutation at a low frequency of 6% in invasive breast tumors of the Carolina Breast Cancer Study (CBCS). The importance of estrogen in breast cancer development is supported by studies demonstrating the occurrence of marked changes in estrogen signaling and in the expression of the two estrogen receptors (ERs), ER alpha and ER beta, during breast tumorigenesis and progression [2,3,4,5,6,7,8]. More recent studies have shown that the ESR1 A908G mutation in codon 303 increases phosphorylation at the Ser305 residue through the P13 kinase/Akt signaling cascade [10], protein kinase A [11], and p21-activated kinase [10], but the downstream functional effects of this phosphorylation remain unclear
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