PRESENCE OF EXON 5-DELETED ESTROGEN-RECEPTOR IN HUMAN BREAST-CANCER -FUNCTIONAL-ANALYSIS AND CLINICAL-SIGNIFICANCE

A variant form of the human oestrogen receptor (ER) mRNA lacking seque nces encoded within exon 5 has been described (Fuqua SAW, Fitzgerald S D, 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 usi ng reverse transcriptase polymerase chain reaction (RT - PCR). HE Delt a 5 mRNA was present in only 13% of non-malignant breast tissues compa red with 32% of carcinomas (95% Cl, P = 0.05). Presence of the HE Delt a 5 mRNA was associated with the presence of immunohistochemically det ected ER (p = 0.015) and progesterone receptor (PR) (P = 0.02). There was a positive correlation between the presence of HE Delta 5 and dise ase-free survival (P = 0.05), suggesting that the presence of HE Delta 5 may be an indicator of better prognosis. We have raised a monoclona l 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 s how that HE Delta 5 protein is present in breast cancer using immunohi stochemical techniques. We also analysed trans-activation by HE Delta 5 in mammalian cells and showed that, in MCF-7 cells, HE Delta 5 compe tes with wild-type ER to inhibit ERE-dependent trans-activation. Our r esults indicate that this variant is unlikely to be responsible for en docrine resistance of breast cancer, but its presence at both the mRNA and protein level suggest that it may, nevertheless, be involved in r egulating the expression of oestrogen-responsive genes in brest cancer .