Abstract

Introduction

Materials & Methods

Results

Discussion & Conclusion

References

Discussion
Board

Estrogen receptors alpha (ER-a) and beta (ER-b) are thought to mediate the action of estradiol in target tissues. These two receptors, which belong to the steroid/retinoic acid/thyroid receptor superfamily, contain several structural and functional domains encoded by two mRNAs containing 8 exons. Upon ligand binding, ER-a and ER-b proteins recognize specific estrogen responsive elements (EREs) located in DNA in the proximity of target genes, and through interactions with several co-activators modulate the transcription of these genes.

Several ER-a and ER-b variant mRNAs have been identified in both normal and neoplastic human tissues (1, 2). Most of these variants contain a deletion of one or more exons of the wild-type ER mRNA. The putative proteins encoded by these variant mRNAs would therefore be missing some functional domains of the wild-type receptors and might interfere with wild-type ER signaling pathways. Indeed, in vitro functional studies have shown that some recombinant ER-a variant proteins can affect estrogen regulated gene transcription. For example, ERD3, the variant protein encoded by exon 3 deleted ER-a mRNA, that is missing the second zinc finger of the DNA binding domain, has been shown to have a dominant negative activity on wild-type ER-a receptor action (3). A similar dominant negative activity has been observed for ERD5 variant protein, encoded by an ER-a variant mRNA deleted in exon 5 sequences, that is missing a part of the hormone binding domain of the wild-type molecule (4). Interestingly, a constitutive hormone independent activity (5) and a wild-type enhancing activity (6) have also been attributed to ERD5 variant protein in different systems.

The discovery that these ER-a variants are expressed in both normal and neoplastic human breast tissues raised the question of their possible role in breast tumorigenesis. We have previously reported an increased relative expression of ERD5 mRNA and of ERC4 mRNA, another ER-a variant mRNA truncated of all sequences following the exon 2 of the wild-type ER-a, in breast tumor samples versus independent normal breast tissues (7-9). In contrast, Erenburg et al. reported recently a decreased relative expression of ERD3 mRNA in tumor tissues and cancer cell lines versus independent normal reduction mammoplasty samples (10).

These data, which suggested that alteration in ERD5, ERD3 and clone 4 mRNA expression may occur during breast tumorigenesis, were obtained in tissues from different individuals and possible inter-individual differences cannot be excluded. In order to clarify this issue, we investigated the expression of these three variant mRNAs in normal breast tissues and their matched adjacent primary breast tumor tissues.

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