Relationship of coregulator and oestrogen receptor isoform expression to de novo tamoxifen resistance in human breast cancer

Abstract

This study addresses the hypothesis that altered expression of oestrogen receptor-beta and/or altered relative expression of coactivators and corepressors of oestrogen receptors are associated with and may be mechanisms of de novo tamoxifen resistance in oestrogen receptor positive breast cancer. All cases were oestrogen receptor +, node negative, primary breast tumours from patients who later had no disease progression (tamoxifen sensitive) or whose disease progressed while on tamoxifen (tamoxifen resistant). Using an antibody to oestrogen receptor-beta that detects multiple forms of this protein (total) but not an antibody that detects only full-length oestrogen receptor-beta 1, it was found that high total oestrogen receptor beta protein expressors were more frequently observed in tamoxifen sensitive tumours than resistant tumours (Fisher's exact test, P=0.046). However, no significant differences in the relative expression of oestrogen receptor beta2, oestrogen receptor beta5 and full-length oestrogen receptor beta1 RNA in the tamoxifen sensitive and resistant groups were found. Also, when the relative expression of two known coactivators, steroid receptor RNA activator and amplified in breast cancer 1 RNA to the known corepressor, repressor of oestrogen receptor activity RNA, was examined, no significant differences between the tamoxifen sensitive and resistant groups were found. Altogether, there is little evidence for altered coregulators expression in breast tumours that are de novo tamoxifen resistant. However, our data provide preliminary evidence that the expression of oestrogen receptor beta protein isoforms may differ in primary tumours of breast cancer patients who prove to have differential sensitivity to tamoxifen therapy.

Figure 1

Examples of immunohistochemistry using the GC-17 antibody which only recognises the full-length ORβ1: (A) normal human breast tissue; (B) ORβ1 negative human breast tumour, H-score=0; (C) ORβ1 low expressing human breast tumour, H-score=100; (D) ORβ1 high expressing human breast tumour, H-score=150.

Figure 2

Examples of immunohistochemistry using the IgYERβ503 antibody which recognises most ORβ isoforms: (A) normal human breast tissue; (B) ORβ negative human breast tumour, H-score=25; (C) ORβ low expressing human breast tumour, H-score=100; (D) ORβ high expressing human breast tumour, H-score=225.