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

A variant form of the human oestrogen receptor (ER) mRNA lacking sequences encoded within exon 5 has been described (Fuqua SAW, Fitzgerald SD, Chamness GC, Tandon AK, McDonnell DP, Nawaz Z, O'Malloy BW, McGuire WL 1991, Cancer Res 51: 105-109). We have examined the expression of the exon 5-deleted ER (HE Delta 5) mRNA variant in breast biopsies using reverse transcriptase polymerase chain reaction (RT - PCR). HE Delta 5 mRNA was present in only 13% of non-malignant breast tissues compared with 32% of carcinomas (95% Cl, P = 0.05). Presence of the HE Delta 5 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 HE Delta 5 and disease-free survival (P = 0.05), suggesting that the presence of HE Delta 5 may be an indicator of better prognosis. We have raised a monoclonal antibody specific to the C-terminal amino acids of HE Delta 5. This antibody recognized the variant but not the wild-type ER protein. We show that HE Delta 5 protein is present in breast cancer using immunohistochemical techniques. We also analysed trans-activation by HE Delta 5 in mammalian cells and showed that, in MCF-7 cells, HE Delta 5 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 brest cancer.