Estrogen signaling pathway and its imaging in human breast cancer

Abstract

Recent remarkable progress in hormonal therapy has provided great benefit to breast cancer patients, but it also evokes novel issues: how accurately can the efficacy of each hormonal therapy be predicted and how can hormonal therapy-resistant patients be treated? These clinically important issues must be closely related to the biological events in each cancer, such as the alteration of intracellular multiple estrogen signaling pathways and the estrogen-related cancer microenvironment, which has recently revealed by molecular biological studies on estrogen and its receptors. However, the estrogen signaling status in individual breast cancers has not been clarified yet. Here we present the context of these issues and introduce our study of new tools which enable the visualization of estrogen signals in individual cancers. The assessment of estrogen receptor (ER)-a activity in individual cancers or ER-activating ability of the cancer microenvironment in each breast cancer patient revealed several new findings and interesting observations. We hope that these approaches provide new clues about the estrogen-dependent mechanisms of breast cancer development, and will be useful to advance the diagnosis and treatment of breast cancer patients. (Cancer Sci 2009; 100: 1773-1778) Estrogen receptor and hormonal therapy in breast cancer E strogen controls various physiological functions in many target tissues, and is also involved in diseases such as breast cancer, endometrial cancer, vascular disease, osteoporosis, and others. In particular, breast cancer is well recognized to be a crucial tumor in which estrogen and its receptor (ER) regulate development and progression in most cases, and are therefore the most important and effective targets for the therapy of breast cancer.(1) In this article, ER refers to estrogen receptor α unless specified.The efficacy of hormonal therapies targeting estrogen and ER has been established in numerous clinical trials. Current hormonal therapies are performed by two main strategies: inhibition of ER functions by anti-estrogens and deprivation of estrogen production by luteinizing hormone-releasing hormone agonist (pre-menopause) or aromatase inhibitor (post-menopause). Prediction of the efficiency of these therapies has involved using classical molecular biomarkers such as ERα and progesterone receptor.(2) However, approximately one-third of ER-positive patients do not respond to endocrine therapy, while some ER-negative patients are responsive.(3) These discrepancies could result from different estrogenrelated intracellular signaling pathways in breast cancer cells.One of the approaches to analyze the estrogen signaling status in breast cancer is expression profiling of estrogen-regulated genes in cancer cells. Comprehensive gene expression analysis, such as DNA microarray, may be a useful tool to address this issue. So far, we have analyzed estrogen-responsive gene expression profiles among ER-positive cancer cells using comprehensive DNA microarray (4) and, based on the obtained informa...

Estrogen receptor-α directly regulates sensitivity to paclitaxel in neoadjuvant chemotherapy for breast cancer

“…MCF-7-E10 is an estrogen signal reporter cell line, which was derived from MCF-7 cell line via stable transfection of the ERE-GFP gene for the purpose of assessing ER activation [19,20]. Paclitaxel-resistant MCF-7-E10 cells showed resistance to paclitaxel- induced growth inhibition compared with parent MCF-7-E10 cells (Fig.…”

“…All cells were incubated at 37°C under 5% CO 2 in air. MCF-7-E10 cells (E10 cells) were established from the MCF-7 by introducing a plasmid carrying the ERE (estrogen responsive element) fused with tk-GFP (green fluorescent protein) gene, as described previously [19,20]. E2 (17b-estradiol) was purchased from Sigma-Aldrich.…”

“…To assess ERE activation in primary tumor cells, we used Ad-ERE-tk-GFP [20,21]. Cancer tissue specimens were minced to *1 mm 3 after rinsing with PBS and digested with collagenase solution for 20-30 min at 37°C.…”

Estrogen-Related Receptors and Breast Cancer: A Mini Review

“…Like all cancers, breast cancer is a complicated disease and many factors, estrogen in particular, contributes to its development and progression (Kelsey and Bernstein 1996). Although estrogen action is mediated through two receptors (ER (Greene, Gilna et al 1986) and ER (Kuiper, Enmark et al 1996)), 70% of breast cancers express ER which serves as the mediator for estrogen action (Russo, Hu et al 2000;Conzen 2008;Hayashi, Niwa et al 2009). In view of the structural similarity and functional cross-talk of the ERs and ERRs, it is possible that ERRs are also involved in breast cancer biology (review and references therein (Ariazi and Jordan 2006;Riggins, Mazzotta et al 2010)).…”

“…There are many factors that influence breast cancer development and progression with hormone and nuclear receptors playing critical roles. Several reviews have been written on the emerging roles of estrogen and nuclear receptors in breast cancer (reviews (Conzen 2008;Hayashi, Niwa et al 2009;Riggins, Mazzotta et al 2010)). In this review we will focus on the estrogen-related receptor alpha, beta and gamma (ERR , and ).…”