Estrogen Receptor β (ERβ) Level but Not Its ERβcx Variant Helps to Predict Tamoxifen Resistance in Breast Cancer

Abstract

The antiestrogen tamoxifen, a major endocrine therapy of estrogen receptor (ER)-positive breast cancer, is nevertheless inefficient in 30 to 40% of cases for unknown reasons. We retrospectively studied 50 ER-positive primary breast carcinomas. All of the patients had received tamoxifen as the only adjuvant therapy. They were divided into two groups depending on whether they relapsed within 5 years (16 tamoxifen-resistant cases) or did not relapse within 5 years (34 tamoxifen-sensitive cases). The expression of total ER␤ protein, and of ER␤cx protein, was estimated anonymously in formalin-fixed, paraffin-embedded tumor sections, by using specific antibodies and quantifiying nuclear immunostaining with a computer image analyzer. All of the tumors were found to be HER-2/neu-negative by immunohistochemistry.Univariate analysis showed that Scarff-Bloom-Richardsson grade modified by Elston (SBR grade; P < 0.001), tumor size (P ‫؍‬ 0.042), and MIB-1 proliferation index (P ‫؍‬ 0.02) were significantly higher in tamoxifen-resistant tumors. A low level of total ER␤, whether in percentage of positive cells or in quantitative immunocytochemical (QIC) score, was also associated with tamoxifen resistance (P ‫؍‬ 0.004). ER␤cx expression and lymph node status were similar between the two groups. The expression of ER␤ in the total population was positively correlated with ER␤cx (r ‫؍‬ 0.63, P < 0.001), and was independent of the other parameters. In a multivariate analysis, ER␤ expression was the most important variable (P ‫؍‬ 0.001), followed by SBR grade (I؉II versus III; P ‫؍‬ 0.008), and MIB-1 (P ‫؍‬ 0.016).To conclude, tamoxifen resistance is associated with classical variables of aggressive tumors (high SBR grade, proliferation index, and tumor size) but not with node invasiveness. Low ER␤ level is an additional independent marker, better than ER␣ level, to predict tamoxifen resistance.

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

“…In patients treated with chemotherapy as well as TAM, ERβ expression also significantly correlates with increased OS [97,105] and DFS [94,97,104,105]. Higher ERβ expression is observed more frequently in TAM-sensitive breast tumors than in TAM-resistant tumors [113], and lower ERβ is associated with TAM resistance [107,113,114]. One study analyzing 138 postmenopausal patients with invasive cancer observed a trend toward worse outcome in ERβ+ patients treated with TAM, although it was not statistically significant and only seventeen ERβ− tumors were used in this comparison.…”

“…Iwase et al have reported that patients with ERβ+ tumors tend to have a better response to endocrine therapy than those with ERβ− tumors [112]. In breast cancer patients treated with adjuvant TAM, high ERβ expression significantly correlates with increased overall [86,107] and disease-free survival [107], no disease progression [113], or no relapse within five years [93,114]. In patients treated with chemotherapy as well as TAM, ERβ expression also significantly correlates with increased OS [97,105] and DFS [94,97,104,105].…”

“…We found fifteen studies investigating ERβ expression and response to endocrine therapy. Of these, thirteen examined ERβ protein expression using primarily IHC [82,86,87,93,94,97,104,105,107,[111][112][113][114]. Only three of these studies [82,97,107] separate ERβ tumor populations based on ERα status, although the majority of tumors typically contain both subtypes.…”

“…The role of ERβcx has also been investigated in seven studies [18,83,87,105,110,111,114] analyzing protein expression levels (Table 1). Two observed no significant correlation between ERβcx protein expression and response to TAM [111,114], and a third showed no difference in RFS or OS between patients with ERα− only tumors expressing high versus low ERβcx levels [87].…”

“…Two observed no significant correlation between ERβcx protein expression and response to TAM [111,114], and a third showed no difference in RFS or OS between patients with ERα− only tumors expressing high versus low ERβcx levels [87]. However, three studies have utilized ERβcx-specific C-terminal antibodies to show that ERβcx expression significantly correlates with increased OS [105], increased RFS [83], and a longer survival rate [110] in a total of 314 patients treated with adjuvant or neoadjuvant endocrine therapy.…”