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

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 . Thirty-seven patients with metastatic ERα+/HER2- breast cancer were included in this study. All the patients in this cohort were female with a median age of 56 years (range 27-78). The patients were predominantly Caucasian (35, 95%) and most women were postmenopausal (23, 66%). The objective was to determine the mRNA expression levels of the genes which are targets of ER-AP1 mediated transcription and AP1 independent ER mediated transcription including CCND1, MYC, IGF-1, Bcl-2, MMP-1, FN1, IGFBP-4, E2F4, CXCL12, PGR, EBAG9, and TRIM25 and correlated with ESR1 and ESR2.