Genomic actions of estrogen receptor α: what are the targets and how are they regulated?

Welboren, Willem‐Jan; Sweep, Fred C.G.J.; Span, Paul N.; Stunnenberg, Hendrik G.

doi:10.1677/erc-09-0086

Cited by 144 publications

(130 citation statements)

References 126 publications

(99 reference statements)

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“…Oestradiol exerts its effects after binding to oestrogen receptors alpha (ERa) and ERb (Kim & Levin 2006, Madak-Erdogan et al 2008, Levin 2009, 2014b, Welboren et al 2009, Chambliss et al 2010, SchultzNorton et al 2011, Filardo & Thomas 2012, Arnal et al 2013, Hamilton et al 2014, Magnani & Lupien 2014. The predominant actions are mediated through the direct binding of the receptor to oestrogen response elements (EREs) in the nucleus and the initiation of transcription or by tethering to other transcription factors, such as AP1 and SP1, with DNA binding to their respective response elements.…”

Section: Molecular Mechanisms Of Action Of Oestrogensmentioning

confidence: 99%

Celebrating 75 years of oestradiol

Simpson

Santen

2015

Journal of Molecular Endocrinology

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Oestrogens exert important effects on the reproductive as well as many other organ systems in both men and women. The history of the discovery of oestrogens, the mechanisms of their synthesis, and their therapeutic applications are very important components of the fabric of endocrinology. These aspects provide the rationale for highlighting several key components of this story. Two investigators, Edward Doisy and Alfred Butenandt, purified and crystalized oestrone nearly simultaneously in 1929, and Doisy later discovered oestriol and oestradiol. Butenandt won the Nobel Prize for this work and Doisy's had to await his purification of vitamin K. Early investigators quickly recognized that oestrogens must be synthesized from androgens and later investigators called this process aromatization. The aromatase enzyme was then characterized, its mechanism determined, and its structure identified after successful crystallization. With the development of knock-out methodology, the precise effects of oestrogen in males and females were defined and clinical syndromes of deficiency and excess described. Their discovery ultimately led to the development of oral contraceptives, treatment of menopausal symptoms, therapies for breast cancer, and induction of fertility, among others. The history of the use of oestrogens for postmenopausal women to relieve symptoms has been characterized by cyclic periods of enthusiasm and concern. The individuals involved in these studies, the innovative thinking required, and the detailed understanding made possible by evolving biologic and molecular techniques provide many lessons for current endocrinologists. Discovery of oestrogenThe concept that substances secreted by one organ could then be transported internally to another via the blood stream is the underpinning of the field of endocrinology. The 'father of physiology', Claude Bernard, articulated the concept of internal secretion by describing how the liver produces glucose, which then travels to and is utilized by other tissues in the body. This concept underlies studies on the ovaries, which became a focus of investigation later in the century. In 1896, Emil Knauer, a 29-year-old Austrian, excised the ovaries of adult rabbits and then re-implanted pieces into different locations in the same animals (Watkins 2007 Doisy then enlisted a nurse in the obstetrics clinic to supply each pregnant patient with a 1 gal jug and ask for her urine. This provided the needed material but was fraught with difficulties. Suspected to be a bootlegger because of the large jugs of yellow material in his car, one of Doisy's drivers was nearly arrested until he suggested using the sniff test with the response 'My god, it is urine'. Doisy, then being recruited to St Louis University, continued his efforts to purify the active substance. Each extract was tested with a bioassay and its effect on uterine stimulation. Urine, the material of choice for study, was initially extracted with a very large countercurrent apparatus (Fig. 1). Costing the exorbitan...

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Section: Molecular Mechanisms Of Action Of Oestrogensmentioning

confidence: 99%

Celebrating 75 years of oestradiol

Simpson

Santen

2015

Journal of Molecular Endocrinology

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“…Welboren et al used ChIP-seq technology to explore ERBS and binding sites for RNA polymerase II in the MCF-7 genome in response to estradiol (E2) and antiestrogen, tamoxifen, or fulvestrant [66] . They identified the 10 205 E2-regulated ERBSs in MCF-7 cells and showed that tamoxifen and fulvestrant partially decrease the binding of ERα and RNA polymerase II around the E2-upregulated genes [66,67] . To examine the role of FOXA1 in ERα binding, Hurtado et al performed ChIPseq analysis of ER binding sites in MCF-7 cells in which FOXA1 was silenced with short interfering RNAs (siRNAs) [68] .…”

Section: Identification Of Estrogen-responsive Genes Using Highthrougmentioning

confidence: 99%

Identification of estrogen-responsive genes based on the DNA binding properties of estrogen receptors using high-throughput sequencing technology

2014

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Estrogens are important endocrine hormones that control physiological functions in reproductive organs, and play a pivotal role in the generation and progression of breast cancer. Therapeutic drugs including anti-estrogen and aromatase inhibitors are used to treat patients with breast cancer. The estrogen receptors, ERα and ERβ, function as hormone-dependent transcription factors that directly regulate the expression of their target genes. Therefore, a better understanding of the function and regulation of estrogen-responsive genes provides insight into the gene regulation network associated with breast cancer. Recent technological developments in highthroughput sequencing have enabled the genome-wide identification of estrogen-responsive genes. Further elucidating the estrogen gene cascade is critical for advancements in the diagnosis and treatment of breast cancer.

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“…After proving that estrogens (17-β estradiol and genistein) increase both the number and sizes of tertiary tumorspheres as well as the level of proliferation marker PCNA, we demonstrated that both the hormones markedly increase PI-9 level in tumorspheres, suggesting their involvement in PI-9 upregulation. Estrogens are known to regulate different cellular processes stimulating both genomic and non-genomic pathways (3)(4)(5)(6)(7)(8). The classical mechanism of estrogen action involves the binding of the hormones to specific nuclear receptors (ERα66, its splice variant ERα46, and the closely related estrogen receptor ERβ) (7,8) which bind to estrogen responsive elements (EREs) located in the promoter of target genes (8).…”

Section: Discussionmentioning

confidence: 99%

“…Approximately 75% of BC cases is characterized by the presence of hormone receptors (ERs) whose expression is considered an important prognostic and therapeutic indicator (2)(3)(4). ERs are nuclear receptors that regulate the transcription of estrogen-responsive genes in target cells after ligand binding and dimerization (5,6).…”

Section: Introductionmentioning

confidence: 99%

The analysis of estrogen receptor-α positive breast cancer stem-like cells unveils a high expression of the serpin proteinase inhibitor PI-9: Possible regulatory mechanisms

Lauricella

Carlisi

Giuliano

et al. 2016

International Journal of Oncology

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Abstract. Breast cancer stem cells seem to play important roles in breast tumor recurrence and endocrine therapy resistance, although the underlying mechanisms have not been well established. Moreover, in some tumor systems the immunosurveillance failure against cancer cells has been related to the presence of the granzyme B inhibitor PI-9. This study explored the status of PI-9 in tumorspheres isolated from estrogen receptor-α positive (ERα + ) breast cancer MCF7 cells. Studies were performed in tertiary tumorspheres which possess high levels of stemness markers (Nanog, Oct3/4 and Sox2) and selfrenewal ability. The exposure to estrogens (17-β estradiol and genistein) increased the number and sizes of tumorspheres, promoting cell proliferation as demonstrated by the increase in the proliferating cell nuclear antigen (PCNA). The study of the three isoforms (66, 46 and 36 kDa) of ERα disclosed that tertiary tumorspheres exhibit a marked increase in ERα36, while the level of ERα66, which is highly expressed in MCF7 cells, declines. Although it is known that PI-9 is a transcriptional target of ERα66, surprisingly in tertiary tumorspheres, despite the reduced level of ERα66, the protein and mRNA content of PI-9 is higher than in MCF7 cells. Treatment with estrogens further increased PI-9 level while decreased that of ERα66 isoform thus excluding the involvement of this receptor isoform in the event. Moreover, our studies also provided evidence that tertiary tumorspheres express elevated levels of CXCR4 and phospho-p38, suggesting that the high PI-9 content might be ascribed to the activation of the proliferative CXCR4/phospho-p38 axis. Taken together, these events could supply a selective advantage to breast cancer stem cells by interfering with immunosurveillance systems and open up the avenue to new possible targets for breast cancer treatment.

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Genomic actions of estrogen receptor α: what are the targets and how are they regulated?

Cited by 144 publications

References 126 publications

Celebrating 75 years of oestradiol

Celebrating 75 years of oestradiol

Identification of estrogen-responsive genes based on the DNA binding properties of estrogen receptors using high-throughput sequencing technology

The analysis of estrogen receptor-α positive breast cancer stem-like cells unveils a high expression of the serpin proteinase inhibitor PI-9: Possible regulatory mechanisms

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