The estrogen receptor (ER) is a ligand-activated enhancer protein that is a member of the steroid/nuclear receptor superfamily. Two genes encode mammalian ER: ERα and ERβ. ER binds to specific DNA sequences called estrogen response elements (EREs) with high affinity and transactivates gene expression in response to estradiol (E2). The purpose of this review is to summarize how natural and synthetic variations in the ERE sequence impact the affinity of ER–ERE binding and E2-induced transcriptional activity. Surprisingly, although the consensus ERE sequence was delineated in 1989, there are only seven natural EREs for which both ERα binding affinity and transcriptional activation have been examined. Even less information is available regarding how variations in ERE sequence impact ERβ binding and transcriptional activity. Review of data from our own laboratory and those in the literature indicate that ERα binding affinity does not relate linearly with E2-induced transcriptional activation. We suggest that the reasons for this discord include cellular amounts of coactivators and adaptor proteins that play roles both in ER binding and transcriptional activation; phosphorylation of ER and other proteins involved in transcriptional activation; and sequence-specific and protein-induced alterations in chromatin architecture.

/pdf/estrogen-receptor-interaction-with-estrogen-response-1cwbzq9jxr.pdf

Estrogen receptor interaction with estrogen response elements.

The Kiss1 gene encodes a family of neuropeptides called kisspeptins, which activate the receptor G protein-coupled receptor-54 and play a role in the neuroendocrine regulation of GnRH secretion. We examined whether estradiol (E2) regulates KiSS-1 in the forebrain of the female mouse by comparing KiSS-1 mRNA expression among groups of ovary-intact (diestrus), ovariectomized (OVX), and OVX plus E2-treated mice. In the arcuate nucleus (Arc), KiSS-1 expression increased after ovariectomy and decreased with E2 treatment. Conversely, in the anteroventral periventricular nucleus (AVPV), KiSS-1 expression was reduced after ovariectomy and increased with E2 treatment. To determine whether the effects of E2 on KiSS-1 are mediated through estrogen receptor (ER)alpha or ERbeta, we evaluated the effects of E2 in OVX mice that lacked functional ERalpha or ERbeta. In OVX mice that lacked functional ERalpha, KiSS-1 mRNA did not respond to E2 in either the Arc or AVPV, suggesting that ERalpha is essential for mediating the inhibitory and stimulatory effects of E2. In contrast, KiSS-1 mRNA in OVX mice that lacked functional ERbeta responded to E2 exactly as wild-type animals. Double-label in situ hybridization revealed that virtually all KiSS-1-expressing neurons in the Arc and AVPV coexpress ERalpha, suggesting that the effects of E2 are mediated directly through KiSS-1 neurons. We conclude that KiSS-1 neurons in the Arc, which are inhibited by E2, may play a role in the negative feedback regulation of GnRH secretion, whereas KiSS-1 neurons in the AVPV, which are stimulated by E2, may participate in the positive feedback regulation of GnRH secretion.

/pdf/regulation-of-kiss1-gene-expression-in-the-brain-of-the-2n23w1irri.pdf

Regulation of Kiss1 gene expression in the brain of the female mouse.

Breast cancer evolution and tumor progression are governed by the complex interactions between steroid receptor [estrogen receptor (ER) and progesterone receptor] and growth factor receptor signaling. In recent years, the field of cancer therapy has witnessed the emergence of multiple strategies targeting these specific cancer pathways and key molecules (ER and growth factor receptors) to arrest tumor growth and achieve tumor eradication; treatment success, however, has varied and both de novo (up front) and acquired resistance have proven a challenge. Recent studies of ER biology have revealed new insights into ER action in breast cancer and have highlighted the role of an intimate crosstalk between the ER and HER family signaling pathways as a fundamental contributor to the development of resistance to endocrine therapies against the ER pathway. The aim of this review article is to summarize the current knowledge on mechanisms of resistance of breast cancer cells to endocrine therapies due to the crosstalk between the ER and the HER growth factor receptor signaling pathways and to explore new available therapeutic strategies that could prolong duration of response and circumvent endocrine resistant tumor growth.

Crosstalk between the Estrogen Receptor and the HER Tyrosine Kinase Receptor Family: Molecular Mechanism and Clinical Implications for Endocrine Therapy Resistance

Estrogen influences the physiology of many target tissues in both women and men. The long-term effects of estrogen are mediated predominantly by nuclear estrogen receptors (ERs) functioning as DNA-binding transcription factors. Tissue-specific responses to estrogen therefore result from regulation of different sets of genes. However, it remains perplexing as to what regulatory sequence contexts specify distinct genomic responses. First, this review classifies estrogen response sequences in mammalian target genes. Of note, around one third of known human target genes associate only indirectly with ER, through intermediary transcription factor(s). Then, computational approaches are presented both for refining direct ER-binding sites and for formulating hypotheses regarding the overall genomic expression pattern. Surprisingly, limited evolutionary conservation of specific estrogen-responsive sites is observed between human and mouse. Finally, consideration of the cellular functions of regulated human genes suggests links between particular biological roles and specific types of estrogen response elements, although with the important caveat that only a restricted set of target genes is available. These analyses support the view that specific, hormone-driven gene expression programs can result from the interplay of environmental and cellular cues with the distinct types of estrogen-response sequences.

/pdf/genomic-targets-of-nuclear-estrogen-receptors-3d1c7pr037.pdf

Genomic targets of nuclear estrogen receptors.

How glucocorticoid receptors modulate the activity of other transcription factors: A scope beyond tethering

Estrogen response element sequence impacts the conformation and transcriptional activity of estrogen receptor alpha.

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Estrogen response element sequence impacts the conformation and transcriptional activity of estrogen receptor alpha.