Expression of oestrogen receptor-β in oestrogen receptor-α negative human breast tumours

Abstract

To analyse the phenotype of breast tumours that express oestrogen receptor-b (ERb) alone tissue microarrays were used to investigate if ERb isoforms are associated with specific prognostic markers and gene expression phenotypes in ERa-negative tumours. ERa-negative tumours were positive for ERb1 in 58% of cases (n ¼ 122/210), total ERb in 60% (n ¼ 115/192) and ERb2/cx in 57% of cases (n ¼ 114/199). Oestrogen receptor-b1 and total ERb were significantly correlated with Ki67 (r ¼ 0.28, Po0.0001, n ¼ 209; r ¼ 0.29, Po0.0001, n ¼ 191) and with CK5/6, a marker of the basal phenotype (r ¼ 0.20, P ¼ 0.0106, n ¼ 170; r ¼ 0.18, P ¼ 0.0223, n ¼ 158). ERb2/cx was strongly associated with p-c-Jun and NF-kBp65 (r ¼ 0.53, Po0.0001, n ¼ 93; r ¼ 0.35, Po0.0001, n ¼ 176). This study shows that a range of ERb isoform expression occurs in ERa-negative breast tumours. While expression of ERb1, total and ERb2/cx are correlated, individual forms show associations with certain phenotypes that suggest different roles in subsets of ERanegative cancers. Based on our in vivo observations, ERb may have the potential to become a therapeutic target in the specific subcohort of ERa-negative breast cancers.

ERβ in breast cancer—Onlooker, passive player, or active protector?

“…ERβ protein expression in breast cancer epithelium is associated with elevated levels of the proliferation markers Ki67 and Cyclin A, whereas ERα is associated with decreased levels [98,106]. Ki67 and Cyclin A were expressed at the highest levels in ERα−/ERβ+ tumors, and ERβ protein expression significantly correlated with Ki67 staining in ERα− tumors [82,87,106], suggesting that ERβ may play a role in the proliferation of ERα− breast tumors. In contrast, one group reported an inverse correlation between ERβ protein and Ki67, especially in high grade DCIS [61].…”

“…In general, expression of ERβ is low in these tumors [63,85]. In one instance ERβ was observed in over 40% of the ERα-samples analyzed [86], and ERβ variants such as ERβcx have been noted in up to 60% of ERα-samples [87]. Thus, there may be subpopulations of ERβ+ tumors, with and without ERα, with potentially different phenotypes.…”

“…Thus, there is some evidence supporting potentially separate roles of ERβ in ERα+/ERβ+ (antiproliferative) versus ERα−/ ERβ+ (proliferative) tumors, but additional data focusing on these groups needs to be obtained. A recent study concentrating exclusively on 216 ERα−/ERβ+ tumors defined by IHC and ligand-binding assays noted that the latter group of tumors also expressed markers such as CK5/6 or CK14 of the basal epithelial phenotype, and that ERβ is widely expressed in basal myoepithelium and luminal epithelium in normal breast [87]. Although proliferation and basal phenotype markers are associated with poor survival, the ERα−/ERβ+ patients in this study had no differences in clinical outcome (relapse-free survival-time to progression or OS) that correlated with either high versus low levels of ERβ, or high versus low markers of proliferation or markers of the basal phenotype.…”

“…Although proliferation and basal phenotype markers are associated with poor survival, the ERα−/ERβ+ patients in this study had no differences in clinical outcome (relapse-free survival-time to progression or OS) that correlated with either high versus low levels of ERβ, or high versus low markers of proliferation or markers of the basal phenotype. The authors postulate the wide variety of treatments the cohort received may have influenced this result [87].…”

“…ERβcx protein levels, which in general are more highly expressed in breast cancer tissue versus normal tissue, significantly increase from normal glands to DCIS and invasive cancer [80,108]. Since ERβ and ERβcx are still frequently expressed in ERα-invasive breast tumors [79,87,99,109], they may be potential therapeutic targets in these cancers. A few studies have shown that ERβcx protein expression does not correlate with tumor size, histological grade, or lymph node status [18,83,110].…”