scholarly journals Estrogen receptor-α signaling in post-natal mammary development and breast cancers

2021 ◽  
Author(s):  
Mariam Rusidzé ◽  
Marine Adlanmérini ◽  
Elodie Chantalat ◽  
I. Raymond-Letron ◽  
Surya Cayre ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Mammary Gland ◽  
Cancer Progression ◽  
Cell Lineage ◽  
Estrogen Receptor Α ◽  
Mammary Development ◽  
Breast Cancers ◽  
Molecular Features ◽  
Gland Morphogenesis ◽  
And Function

Abstract17β-estradiol controls post-natal mammary gland development and exerts its effects through Estrogen Receptor ERα, a member of the nuclear receptor family. ERα is also critical for breast cancer progression and remains a central therapeutic target for hormone-dependent breast cancers. In this review, we summarize the current understanding of the complex ERα signaling pathways that involve either classical nuclear “genomic” or membrane “non-genomic” actions and regulate in concert with other hormones the different stages of mammary development. We describe the cellular and molecular features of the luminal cell lineage expressing ERα and provide an overview of the transgenic mouse models impacting ERα signaling, highlighting the pivotal role of ERα in mammary gland morphogenesis and function and its implication in the tumorigenic processes. Finally, we describe the main features of the ERα-positive luminal breast cancers and their modeling in mice.

Calcineurin regulates the stability and activity of estrogen receptor α

2021 ◽  
Vol 118 (44) ◽  
pp. e2114258118
Author(s):  
Takahiro Masaki ◽  
Makoto Habara ◽  
Yuki Sato ◽  
Takahiro Goshima ◽  
Keisuke Maeda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
The Stability ◽  
Positive Breast Cancer

Estrogen receptor α (ER-α) mediates estrogen-dependent cancer progression and is expressed in most breast cancer cells. However, the molecular mechanisms underlying the regulation of the cellular abundance and activity of ER-α remain unclear. We here show that the protein phosphatase calcineurin regulates both ER-α stability and activity in human breast cancer cells. Calcineurin depletion or inhibition down-regulated the abundance of ER-α by promoting its polyubiquitination and degradation. Calcineurin inhibition also promoted the binding of ER-α to the E3 ubiquitin ligase E6AP, and calcineurin mediated the dephosphorylation of ER-α at Ser294 in vitro. Moreover, the ER-α (S294A) mutant was more stable and activated the expression of ER-α target genes to a greater extent compared with the wild-type protein, whereas the extents of its interaction with E6AP and polyubiquitination were attenuated. These results suggest that the phosphorylation of ER-α at Ser294 promotes its binding to E6AP and consequent degradation. Calcineurin was also found to be required for the phosphorylation of ER-α at Ser118 by mechanistic target of rapamycin complex 1 and the consequent activation of ER-α in response to β-estradiol treatment. Our study thus indicates that calcineurin controls both the stability and activity of ER-α by regulating its phosphorylation at Ser294 and Ser118. Finally, the expression of the calcineurin A–α gene (PPP3CA) was associated with poor prognosis in ER-α–positive breast cancer patients treated with tamoxifen or other endocrine therapeutic agents. Calcineurin is thus a promising target for the development of therapies for ER-α–positive breast cancer.

scholarly journals The genomic landscape of estrogen receptor α binding sites in mouse mammary gland

PLoS ONE ◽  
2019 ◽  
Vol 14 (8) ◽  
pp. e0220311 ◽  
Author(s):  
Murugesan Palaniappan ◽  
Loc Nguyen ◽  
Sandra L. Grimm ◽  
Yuanxin Xi ◽  
Zheng Xia ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Mammary Gland ◽  
Binding Sites ◽  
Estrogen Receptor Α ◽  
Mouse Mammary Gland ◽  
Genomic Landscape

scholarly journals Regulation of estrogen receptor α function in oral squamous cell carcinoma cells by FAK signaling

2014 ◽  
Vol 21 (4) ◽  
pp. 555-565 ◽  
Author(s):  
Yi-Lin Chang ◽  
Yu-Kan Hsu ◽  
Tsung-Fan Wu ◽  
Chieh-Ming Huang ◽  
Li-Yin Liou ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Estrogen Receptor ◽  
Cell Growth ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Squamous Cell ◽  
Transcriptional Activity ◽  
Estrogen Receptor Α ◽  
And Function

Estrogen receptor α (ERA) is a DNA-binding transcription factor that plays an important role in the regulation of cell growth. Previous studies indicated that the expression of ERα in cell lines and tumors derived from oral squamous cell carcinoma (OSCC). The aim of this study was to examine the activity and function of ERα in OSCC cells and the mechanism underlying ERα activation. Immunochemical analyses in benign (n=11) and malignant (n=21) lesions of the oral cavity showed that ERα immunoreactivity was observed in 43% (9/21) of malignant lesions, whereas none of benign lesions showed ERα immunoreactivity. The ERα expression was also found in three OSCC cell lines and its transcriptional activity was correlated with cell growth. Addition of estradiol stimulated cell growth, whereas treatment of tamoxifen or knockdown of ERα expression caused reduced cell growth. Interestingly, the expression and activity of focal adhesion kinase (FAK) were associated with the phosphorylation of ERα at serine 118 in OSCC cells. Elevated expression of FAK in the slow-growing SCC25 cells caused increases in ERα phosphorylation, transcriptional activity, and cell growth rate, whereas knockdown of FAK expression in the rapid-growing OECM-1 cells led to reduced ERα phosphorylation and activity and retarded cell growth. Inhibition of the activity of protein kinase B (AKT), but not ERK, abolished FAK-promoted ERα phosphorylation. These results suggest that OSCC cells expressed functional ERα, whose activity can be enhanced by FAK/AKT signaling, and this was critical for promoting cell growth. Thus, FAK and ERα can serve as the therapeutic targets for the treatment of OSCC.

scholarly journals Quantitative Analysis of Estrogen Receptor Proteins in Rat Mammary Gland*

Endocrinology ◽  
2001 ◽  
Vol 142 (7) ◽  
pp. 3177-3186 ◽  
Author(s):  
Shigehira Saji ◽  
Hideki Sakaguchi ◽  
Sandra Andersson ◽  
Margaret Warner ◽  
Jan-Åke Gustafsson
Keyword(s):  
Estrogen Receptor ◽  
Mammary Gland ◽  
Total Protein ◽  
Messenger Rna ◽  
Estrogen Receptor Α ◽  
Lactation Period ◽  
Binding Assays ◽  
Western Blots ◽  
Mean Values ◽  
Rat Mammary Gland

Abstract Estrogen receptor α and β proteins (ERα and ERβ) at various stages of development of the rat mammary gland were quantified by Western blotting. ERα and ERβ recombinant proteins were used as standards, and their molar concentrations were measured by ligand binding assays. In 3-week-old pregnant, lactating, and postlactating rats the ERα content ranged from 0.30–1.55 fmol/μg total protein (mean values). The ERβ content of the same samples ranged between 1.06–7.50 fmol/μg total protein. At every developmental stage, the ERβ content of the mammary gland was higher than that of ERα. When receptor levels were normalized against β-actin, it was evident that ER expression changed during development, with maximum expression of both receptors during the lactation period. With an antibody raised against the 18-amino acid insert of the ERβ variant, originally called ERβ2 but named ERβins in this paper, Western blots revealed that ERβins protein was up-regulated during the lactation period. RT-PCR showed that the levels of messenger RNA of ERβins paralleled those of the protein. Double immunohistochemical staining with anti-ERα and anti-ERβins antibodies revealed that ERβins protein colocalized with ERα in 70–80% of the ERα-expressing epithelial cells during lactation and with 30% of these cells during pregnancy. These observations indicate that expression of ERβins is regulated not only quantitatively, but also with regard to its cellular distribution. As ERβins acts as the dominant repressor of ERα, we suggest that its coexpression with ERα quenches ERα function and may be one of the factors that contribute to the previously described insensitivity of the mammary gland to estrogens during lactation.

scholarly journals Foxl2, a Forkhead Transcription Factor, Modulates Nonclassical Activity of the Estrogen Receptor-α

Endocrinology ◽  
2009 ◽  
Vol 150 (11) ◽  
pp. 5085-5093 ◽  
Author(s):  
So-Youn Kim ◽  
Jeffrey Weiss ◽  
Minghan Tong ◽  
Monica M. Laronda ◽  
Eun-Jig Lee ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Transcription Factor ◽  
Direct Action ◽  
Ovarian Follicle ◽  
Estrogen Receptor Α ◽  
Ovary Development ◽  
Activator Protein 1 ◽  
Forkhead Transcription Factor ◽  
Protein Levels ◽  
And Function

Foxl2 is a forkhead transcription factor required for ovary development and ovarian follicle maturation. In this report, we identified and characterized a functional relationship between Foxl2 expression and estrogen receptor (ER)-α signaling. We show that Foxl2 has no effect on classical ERα-mediated transcription, which occurs through canonical estrogen response elements. However, Foxl2 suppresses ERα signaling through nonclassical tethered transcriptional pathways. Specifically, the selective ER modulator tamoxifen stimulates activator protein-1 (AP1)-dependent transcription via the ERα, and this enhancement is blocked by Foxl2. Two lines of evidence suggest that Foxl2 suppression is mediated by physical interactions with ERα rather than direct action at AP1 binding sites. First, ERα is coimmunoprecipitated with Foxl2. Second, activation of a upstream activating sequence (UAS) reporter by Gal4-cJun in the presence of ERα and tamoxifen was blocked by Foxl2, demonstrating suppression in the absence of an AP1 site. Cyclooxygenase-2 (COX2), which is required for ovulation, was identified through expression profiling as a candidate physiological target for nonclassical ERα signaling and thus modulation by ERα/Foxl2 interactions. This possibility was confirmed by two sets of experiments. COX2 protein levels were induced by ERα in the presence of tamoxifen, and protein expression was suppressed by Foxl2. In addition, ERα stimulation of the COX2 promoter was repressed by Foxl2. We conclude that ERα and Foxl2 interact and that Foxl2 selectively suppresses ERα-mediated transcription of AP1-regulated genes. These data provide a potential point of convergence for ERα and Foxl2 to regulate ovarian development and function.

Role of the proteasome in the regulation of estrogen receptor α turnover and function in MCF-7 breast carcinoma cells

2005 ◽  
Vol 94 (4) ◽  
pp. 347-359 ◽  
Author(s):  
Ioanna Laïos ◽  
Fabrice Journé ◽  
Denis Nonclercq ◽  
Doris Salazar Vidal ◽  
Robert-Alain Toillon ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Breast Carcinoma ◽  
Estrogen Receptor Α ◽  
Carcinoma Cells ◽  
Breast Carcinoma Cells ◽  
And Function ◽  
Mcf 7
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