Pergamon J. Steroid Biochem. Molec. Biol. Vol. 62, No. 5/6, pp. 363-372, 1997 © 1997 Published by Elsevier Science Ltd. All rights reserved Printed in Great Britain PII: 80960-0760(97)00084o8 0960-0760/97 $17.00 + 0.00 MiniReview Estrogen Receptor Variants and Mutations Leigh C. Murphy,* Helmut Dotzlaw, Etienne Leygue, Deborah Douglas, Amanda Coutts and Peter H. Watson Department of Biochemistry and Molecular Biology, University of Manitoba, Winnipeg, R3E OW3, Canada There is a large and increasing body of experimental and clinical data supporting the existence of variant estrogen receptor (ER) proteins in both normal and neoplastic estrogen target tissues, including human breast. Therefore, future examination of ER signal transduction and/or measure- ment of ER protein must take into account variant ER expression. The functions of variant ER pro- teins, either physiolo;#cal or pathological, remain unclear, although a role(s) for some ER variants in breast tumorigenesis and breast cancer progression would be consistent with the accumulated data. Possible tissue .,;pecific expression leads to the speculation that ER variants may have a role in tissue specific estrogen action. The following review focuses on the current knowledge available in the scientific literature with respect to the type and characteristics of estrogen receptor variants and mutations that have been identified to occur naturally in tissues and cell lines. © 1997 Published by Elsevier Science Ltd. All rights reserved J. Steroid Biochem. Molec. BioL, Vol. 62, No. 5/6, pp. 363-372, 1997 INTRODUCTION Estrogens are major regulators of many physiological functions, especially those associated with reproduc- tion and mammary gland development [1]. As well, estrogens are involved in the growth and development of both uterine and mammary cancers [2]. The princi- pal mechanism by which the effects of estrogen are mediated in either normal or neoplastic target cells is via an initial interaction with the estrogen receptor (ER). The ER is a member of the steroid/thyroid/reti- noid receptor gene superfamily [3]. The protein pro- ducts of this family are intracellular ligand-activated transcription factors regulating the expression of sev- eral gene products, which ultimately result in a target tissue specific response. Ligands for the ER include steroidal and nonsteroidal estrogens and antiestrogens [4]. Furthermore, ligand-independent activation of the ER can occur in both normal and neoplastic target cells [5.6]. *Correspondence to L. C. Murphy. Tel: 789 3233; Fax: 783 0864; e-mail: lcmurph@cc.umanJ toba.ca. Received 6 Feb. 1997; accepted 12 Jun. 1997. The effects of estrogen and antiestrogens on various target tissues can be markedly different even at the level of regulation of expression of the same gene in different tissues or cell types [7-10]. Furthermore, it is thought that perturbations of the ER signal transduc- tion pathway are likely to contribute to tumor pro- gression, especially in mammary cancer and the eventual development of a hormone-independent and more aggressive phenotype [11]. One mechanism underlying tissue specific differences and altered responsiveness associated with cancer development and progression could be alterations in the structure and therefore function of the ER itself. This review will focus on structural changes in the ER that have been identified to occur naturally in tissues and cell lines. A LARGE BODY OF MOLECULAR EVIDENCE EXISTS TO SUPPORT THE EXPRESSION OF VARIANT AND MUTANT ER MRNA SPECIES ER-like mRNAs distinct from the wild-type ER mRNA have been identified in many known ER posi- 363