Presence of exon 5-deleted oestrogen receptor in human breast cancer: Functional analysis and clinical significance

Abstract

A variant form of the human oestrogen receptor (ER) mRNA lacking sequences encoded within exon 5 has been described. We have examined the expression of the exon 5-deleted ER (HEΔ5) mRNA variant in breast biopsies using reverse transcriptase polymerase chain reaction (RT-PCR). HEΔ5 mRNA was present in only 13% of non-malignant breast tissues compared with 32% of carcinomas (95% CI, P = 0.05). Presence of the HEΔ5 mRNA was associated with the presence of immunohistochemically detected ER (P = 0.015) and progesterone receptor (PR) (P = 0.02). There was a positive correlation between the presence of HEΔ5 and disease-free survival (P = 0.05), suggesting that the presence of HEΔ5 may be an indicator of better prognosis. We have raised a monoclonal antibody specific to the C-terminal amino acids of HEΔ5. This antibody recognized the Variant but not the wild-type ER protein. We show that HEΔ5 protein is present in breast cancer using immunohistochemical techniques. We also analysed trans-activation by HEΔ5 in mammalian cells and showed that, in MCF-7 cells, HEΔ5 competes with wild-type ER to inhibit ERE-dependent trans-activation. Our results indicate that this variant is unlikely to be responsible for endocrine resistance of breast cancer, but its presence at both the mRNA and protein level suggest that it may, nevertheless, be involved in regulating the expression of oestrogen-responsive genes in breast cancer.