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Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer

ABSTRACT: We found by RNA seq analysis that the expression of the cyclin D1 gene, the classic target of estrogen-stimulated transcription through an AP1 response element, negatively correlated with that of ERβ/ESR2 as measured using Spearman correlation coefficient (rho = -0.45, p = 0.005). ERβ/ESR2 expression was also negatively correlated with that of ERα/ESR1 (rho = -0.35, p = 0.033). However, ERβ/ESR2 mRNA expression positively correlated with that of IGFBP4 (rho = 0.58, p < 0.001) and CXCL12 (rho = 0.54, p < 0.001). The univariate Cox proportional hazards estimate for overall survival by ESR2 expression was 0.54 (95% CI 0.06, 5.22), suggesting a positive trend that did not reach statistical significance in this numerically limited cohort .

ORGANISM(S): Homo sapiens

PROVIDER: GSE198545 | GEO | 2022/05/18

REPOSITORIES: GEO

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Project description:PURPOSE: Estrogen receptor alpha (ERα, encoded by ESR1) is a well-characterized transcription factor expressed in more than 75% of breast tumors and is the key biomarker to direct endocrine therapies. On the other hand, much less is known about estrogen receptor beta (ERβ, encoded by ESR2) and its importance in cancer. Previous studies had some disagreement, however most reports suggested a more favorable prognosis for patients with high ESR2 expression. METHODS: To add further clarity to ESR2 in breast cancer, we interrogated a large population-based cohort of primary breast tumors (n=3207) from the SCAN-B study (Sweden Cancerome Analysis Network—Breast [SCAN-B], ClinicalTrials.gov identifier: NCT02306096). Spearman rank correlation was used to determine correlations between expression of ESR1 and ESR2. Kruskal-Wallis non-parametric test and Wilcoxon rank sum test were used to compare and plot expression of the ESR1 and ESR2 genes in various clinical groups such as PAM50 subtype and age groups in both the SCAN-B and TCGA cohorts. Transformed ESR2 expression data was divided into tertiles, with the first tertile defined as ESR2-high, and the bottom two tertiles at ESR2-low. Mann Whitney U test and Fisher’s exact test were used to evaluate significant differences in the clinicopathological variables for the ESR2-high and ESR2-low groups. Survival analysis was performed by Kaplan-Meier and Cox regression survival analyses that included a median follow-up of 6.2 years (IQR = 2.2). RESULTS: Using RNA-seq data, we found that ESR2 is expressed at low levels overall with a slight inverse correlation to ESR1 expression (Spearman R = -0.18, p = 2.2e-16), and highest ESR2 expression in the basal- and normal-like PAM50 subtypes. ESR2-high tumors had favorable overall survival (p=0.006), particularly in subgroups receiving endocrine therapy (p=0.03) and in triple-negative breast cancer (p=0.01). These results were generally robust in multivariable analyses accounting for patient age, size, node status, and grade. Gene modules consistent with immune response were associated to ESR2-high tumors. CONCLUSIONS: Taken together, our results indicate that ESR2 is generally expressed at low levels in breast cancer but associated with improved overall survival and may be related to immune response modulation.

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Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer

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