Estrogen and progesterone receptor gene polymorphisms and sporadic breast cancer risk: A Spanish case‐control study

Abstract

Estrogens, and to a lesser extent progesterones, influence the proliferation, differentiation and physiology of breast tissue as well as the development and progression of breast cancer. Genetic variants in the steroid hormone receptor genes ESR1 and PGR (belonging to the nuclear receptor superfamily) could therefore modify sporadic breast cancer susceptibility. Two studies have shown a protective effect associated with variants in ESR1 in 2 distinct populations. We studied 4 single nucleotide polymorphisms (SNPs) in ESR1 and 4 in PGR in 550 consecutive and unrelated sporadic Spanish breast cancer patients and 564 healthy Spanish controls. We observed a dominant protective effect for the S10S variant in ESR1, with an estimated odds ratio (OR) of 0.75 (95% CI 5 0.58-0.97; p 5 0.03) although functional studies did not show changes in the RNA stability. A small subset of individuals carried a haplotype combination that corroborates this protection. No other SNP considered in either gene was found to be associated with sporadic breast cancer. Our results obtained in a European population confirm the protective role of the S10S variant in ESR1, previously reported in an Asian and a European-American population. ' 2006 Wiley-Liss, Inc.

Potentially functional polymorphisms in ESR1 and breast cancer risk: a meta-analysis

“…One study gets protective effect for variant genotypes of synonymous SNP rs2077647 but reported that the variant neither alter mRNA expression nor predicted RNA splicing [18]. We presume that this association may be due to relative higher LD between rs2077647 and rs2234693 for both Asians (r 2 = 0.77) and Caucasians (r 2 = 0.73).…”

“…However, it has not consistently been found to be associated with risk of breast cancer [5][6][7][8][9][10][11][12][13][14][15]. Other studies, examining more extensive ESR1 SNPs with breast cancer risk are also inconclusive [16][17][18][19][20][21].…”

“…ESR1 has more than 1,400 reported single nucleotide polymorphisms (SNPs), but none common [minor allele frequency (MAF) [0.05] synonymous SNPs (with amino acid substitutions). Several potentially functional SNPs in ESR1 have been evaluated for their association with breast cancer (Table 1; [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]) as well as other estrogen related phenotypes [22][23][24][25][26][27]. For example, a SNP in ESR1 intron 1 (rs2234693) has been found to produce a binding site for the transcription factor B-myb and has been suggested to increase transcription or produce ERa isoforms with different properties [28].…”

TGF-B signaling pathway, ER-a and the heterogeneity of breast cancer risk among hispanic and non-hispanic white women.

“…Most published association studies have evaluated the most common SNPs of ERα: PvuII (397T > C, rs2234693) and the XbaI (351A > G, rs9340799) restriction fragment length polymorphisms, both located in intron 1 and found to be in LD [179]. There are mixed results for these two SNPs reported from several studies [180][181][182][183][184][185][186][187]. In a meta-analysis of AA genotype of XbaI (rs9340799) [188].…”

“…Although its functionality is not well established, this region seems to alter the ERα expression [189]. A meta-analysis, conducted by Li and colleagues [188], pooled data from three studies [180,[182][183] and no association was observed (estimate not given). Lastly, two studies have reported an increase in risk: a small study (n=192) conducted in Romania [189] reported a >2-fold increase in risk (per-allele); and a study conducted in the United Kingdom with ~3,900…”