Extracellular matrix integrity: A possible mechanism for differential clinical effects among selective estrogen receptor modulators and estrogens?

Abstract

Recent gene microarray studies have illustrated heterogeneity in gene expression changes not only between estrogens and selective estrogen receptor modulators (SERMs), but also across different SERM molecules. In ovariectomized rats, this phenomenon was observed with respect to a number of genes involved in collagen turnover and extracellular matrix (ECM) integrity in the uterus and vaginal tissues. Preliminary mechanistic data suggest that these effects on ECM integrity may have relevance in the context of the effect of estrogens and some SERMs to increase the risk of pelvic organ prolapse and the incidence of urinary incontinence in postmenopausal women. Given the pivotal role of ECM integrity and collagen turnover in other tissues and disease states, these processes may provide a fruitful target for future research into the mechanisms for the heterogeneous pharmacology of estrogens and SERMs across different cell types and target tissues.

Introduction

Estrogen exerts a broad spectrum of effects in many different tissues via interaction with and activation of estrogen receptors (ER's). ERs are ligand-activated transcription factors with six structural domains of overlapping function. In the absence of ligand, ER exists as a monomeric, latent form and can be found in either the cytosol or the nucleus. Upon estrogen binding, a conformational change is induced in the receptor that favors ER dimerization and recruitment of co-factors that form a transcriptional complex. This ligand-bound complex is then translocated into the nucleus where it can bind either directly to a specific upstream element in the promoter region of estrogen-responsive genes, termed the estrogen response elements (ERE), or indirectly to other upstream promotor elements via complexes with other proteins, ultimately causing a change in gene expression that leads to a change in cell function. More recently, a controversial proposal of possible non-nuclear receptors for estrogen associated with the cell membrane has been described that may mediate some of the rapid, non-genomic effects of estrogens (Hisamoto and Bender, 2005, Sak and Everaus, 2004).

Selective ER modulators (SERMs) are a structurally diverse family of molecules that bind with high affinity to and modulate the activity of ER's, but can act as ER agonists, partial agonists, or antagonists in a tissue-dependent manner (McDonnell, 2004). Included in this family of molecules are triphenylethylene compounds such as tamoxifen, toremifene, clomiphene, idoxifene, and droloxifene; benzothiophenes such as raloxifene and arzoxifene; the centchroman-related (benzopyran) compound levormeloxifene; the tetrahydronaphthalene lasofoxifene; and the indole bazedoxifene. SERMs currently in clinical use include tamoxifen for the prevention and treatment of breast cancer, toremifene for the treatment of breast cancer, clomiphene for the induction of ovulation, and raloxifene for the prevention and treatment of postmenopausal osteoporosis.

The development of multiple SERMs and their subsequent preclinical and clinical characterization has demonstrated that the pharmacology of these ER ligands is complex. It is now apparent that in addition to structural diversity, the SERMs produce different conformations of the SERM-bound ER complex which in turn can induce different effects not only between tissues, but also within the same cell type or target tissue. Heat map analyses of global gene expression in bone cells (Kian et al., 2004) and human breast cancer cells (Frasor et al., 2004, Levenson et al., 2002) have revealed substantial differences in gene expression changes induced by structurally distinct SERMs. These results support the general concept that different SERMs can evoke heterogeneous effects on gene expression, and ultimately cell function, within the same tissue. However, our understanding of how different SERM-induced gene expression profiles contribute to variant clinical outcomes remains very limited. This article reviews recent evidence suggesting that differential effects of ER ligands on factors involved in extracellular matrix (ECM) integrity and collagen turnover may play a role in at least some of the diverse clinical effects of these molecules.