Elevated Aromatase (CYP19A1) Expression Is Associated with a Poor Survival of Patients with Estrogen Receptor Positive Breast Cancer

Abstract

Genetic variants in CYP19A1, the gene encoding aromatase, have been reported to be associated with circulating estrogen concentrations, a key risk factor for breast cancer. The mechanism underlying this association is still unclear; it has been suggested that some of these variants may alter the expression and/or activity of aromatase. Here we analyzed the expression of intra-tumoral CYP19A1 messenger RNA (mRNA) and the genotypes of rs10046, a well-characterized single nucleotide polymorphism in CYP19A1, in 138 breast cancer patients and 15 breast cancer cell lines. The genotype TT was detected in 36 patients and six cell lines, genotype CT in 55 patients and five cell lines, and genotype CC in 28 patients and four cell lines. We found no evidence for a significant association of CYP19A1 levels with rs10046 genotypes, although expression tended to be higher in tumors and cell lines with the homozygous risk genotype TT. We also found no evidence for a significant association of rs10046 genotypes with breast cancer prognosis. In contrast, high CYP19A1 expression was highly significantly associated with a poor overall, disease-free, and metastasis-free survival in estrogen receptor-positive but not negative breast cancer patients. Moreover, CYP19A1 mRNA was significantly elevated in postmenopausal patients and in patients older than 50 years, and a trend towards a positive correlation with ER status and ESR1 mRNA expression was observed. These findings highlight the key role of aromatase in estrogen receptor-positive breast cancer biology.Electronic supplementary materialThe online version of this article (10.1007/s12672-017-0317-2) contains supplementary material, which is available to authorized users.

Association of the MDM2 SNP285 and SNP309 Genetic Variants with the Risk, Age at Onset and Prognosis of Breast Cancer in Central European Women: A Hospital-Based Case-Control Study

“…Differences between two groups with respect to age at onset were analyzed by two-sided t -tests, and between three or more groups by ANOVA. Statistical methods of survival analyses, as well as follow-up details of our study population have been described in References [46,72]. p -Values to Kaplan-Meier analyses and analyses of the cumulative breast cancer incidence were calculated by log-rank tests, as described in Reference [73].…”

Cytoplasmic PPARγ is a marker of poor prognosis in patients with Cox-1 negative primary breast cancers

“…Our finding of a strong correlation between Cox-1 and cytoplasmic PPARγ highlight their possible interaction in BC cells. Furthermore, Cox-1 and Cox-2 expression has been shown to be strongly associated in BC to the expression of the aromatase (CYP19A1) [55] which has been shown to be associated with a poor survival of ER positive BC patients [56]. As a consequence, the link of cytoplasmic PPARγ with poor survival might involve the dysregulation of CYP19A1 expression through Cox activity.…”

The 40bp Indel Polymorphism rs150550023 in the MDM2 Promoter is Associated with Intriguing Shifts in Gene Expression in the p53-MDM2 Regulatory Hub

“…Isolation of total RNA from 111 fresh-frozen tumor samples with TRIreagent (Sigma, Vienna, Austria), quality control of the isolated RNA with the Bioanalyzer 2100 (Agilent, St. Clara, USA), reverse transcription with the High-Capacity cDNA Archive Kit (Applied Biosystems, Brunn/Gebirge, Austria), and quantification of relative mRNA levels of MDM2 , p53, BAX , PERP, and p21 has been described previously [ 66 , 77 ]. Briefly, each sample was analyzed in duplicate by a quantitative reverse transcription PCR (qRT-PCR; real-time PCR) with an Applied Biosystems 7500 fast instrument, using the following primers and gene-specific probes obtained from Applied Biosystems: MDM2 , hs00234753_m1; p53, hs_001533340_m1; BAX , hs00414514_m1; PERP , hs00953482_g1; p21, hs00355782_m1; and β-actin (control), hs_99999903_m1.…”

“…Four non-cancer cell lines were used as normalization controls for the analyses in breast cancer cell lines (HMEC, Hs578Bst, MCF10A, and MCF10F; indicated as open circles in Figure 4 ). All relative mRNA expression levels are presented as 2 −ΔΔCt values (i.e., as linear values, but on a logarithmic ordinate) as described [ 66 , 77 ].…”

“…Correlations between expression levels of two genes were analyzed by determining Spearman’s rank correlation coefficients (rho/ρ/r) and corresponding p -values. Follow-up details of our study population have been described [ 66 , 77 ]. The overall and metastasis-free survival was analyzed by univariable and multivariable Cox proportional hazard models, and included the variables rs150550023 genotype, SNP309 genotype, TP53 status, ER status, and PR status.…”