EXON-5 DELETION VARIANT ESTROGEN-RECEPTOR MESSENGER-RNA EXPRESSION IN RELATION TO TAMOXIFEN RESISTANCE AND PROGESTERONE-RECEPTOR-PS2 STATUS IN HUMAN BREAST-CANCER

The exon 5 deletion splice variant of estrogen receptor (Delta 5 ER), which in vitro is constitutively active in the absence of estrogens, may have a role in conferring both tamoxifen resistance and ER-related phenotype in breast cancer. We have investigated the expression of this variant in vivo (at the level of mRNA) in relation to known tamoxifen resistance and expression of the estrogen-regulated genes progesterone receptor (PgR) and pS2. The amount of Delta 5 ER mRNA relative to wild type (WT) ER mRNA (%Delta 5/WT) was assayed in 70 tamoxifen-resistant and 50 primary breast carcinomas using reverse transcription/PCR. Both WT and Delta 5 ER mRNA were detected in the majority of tumors, although Delta 5 ER was detected only in the presence of WT ER. Overall no significant difference was seen in %Delta 5/WT ER between tamoxifen-resistant and primary control tumors (medians, 13 and 15%, respectively). Tumors in both control and resistant groups which expressed PgR/pS2 in the absence of measurable ER protein (ER- PgR+ and ER- pS2+) had significantly higher Delta 5 ER mRNA levels compared with other phenotypes (P < 0.002). This association with ER-/pS2+ tumors has not been demonstrated previously. In ER+ tumors which expressed pS2, significantly greater Delta 5 ER mRNA expression was observed in tamoxifen-resistant compared with control tumors (P = 0.05). A similar although nonsignificant trend was observed in ER+ PgR+ tumors. While Delta 5 ER mRNA is unlikely to be responsible for tamoxifen resistance in most breast cancers, elevated Delta 5 ER mRNA levels may be important in some tumors, especially those which continue to express high levels of PgR/pS2.