scholarly journals 2’, 3’, 4’-Trihydroxychalcone Changes Estrogen Receptor Α Regulation of Genes and Breast Cancer Cell Proliferation by a Reprogramming Mechanism

2021 ◽  
Author(s):  
Candice B Herber ◽  
Chaoshen Yuan ◽  
Anthony Chang ◽  
Jen-Chywan Wang ◽  
Isaac Cohen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Gene Regulation ◽  
Estrogen Receptor ◽  
Adverse Effects ◽  
Binding Site ◽  
Binding Studies ◽  
Long Term Treatment ◽  
Mcf 7

Abstract BackgroundMenopausal hormone therapy (MHT) is recommended for only five years to treat vasomotor symptoms and vulvovaginal atrophy because of safety issues with long-term treatment. We examined the ability of 2’, 3’, 4’-trihydroxychalcone (2’, 3’, 4’-THC) to modulate ERα-mediated responses on gene regulation and cell proliferation to identify drugs that can potentially overcome the adverse effects of estradiol (E2) in MHT so it can be used for long-term therapy to treat prolonged menopausal symptoms and prevent chronic diseases. MethodsTransfection assays, quantitative real time-polymerase chain reaction, and microarrays were used to evaluate the effects of 2’, 3’, 4’-THC on gene regulation. Radioligand binding studies were used to determine if 2’, 3’, 4’-THC binds to ERα. The effects of 2’, 3’, 4’-THC on cell proliferation and the cell cycle were examined in MCF-7 breast cancer cells using growth curves and flow cytometry. Western blots were used to determine if 2’, 3’, 4’-THC alters the E2 activation of the MAPK pathway and degradation of ERα. Chromatin immunoprecipitation was used to measure ERα binding to genes. Results2’, 3’, 4’-THC produced a synergistic response of E2 activation of reporter and endogenous genes in U2OS osteosarcoma cells. Microarrays identified 824 genes that we termed reprogrammed genes because they were not regulated in U2OS-ERα cells unless the cells were treated with 2’, 3’, 4’-THC and E2 together. 2’, 3’, 4’-THC blocked the proliferation of MCF-7 cells by preventing the E2-induced stimulation of MAPK activity and c-MYC transcription. The antiproliferative mechanism of 2’, 3’, 4’-THC differs from selective estrogen receptor modulators (SERMs) since 2’, 3’, 4’-THC does not bind to E2 binding site in ERα like SERMs. ConclusionOur study identified 2’, 3’, 4’-THC as a reprogramming compound, because it changes the actions of E2 on gene regulation and cell proliferation without competing for the E2 binding site in ERα. The addition of a reprogramming compound such as 2’, 3’, 4’-THC to estrogens in MHT may offer a new strategy to overcome the adverse effects of estrogen in MHT through a reprogramming mechanism rather than an antagonist action.

scholarly journals Unique Roles of p160 Coactivators for Regulation of Breast Cancer Cell Proliferation and Estrogen Receptor-α Transcriptional Activity

Endocrinology ◽  
2008 ◽  
Vol 150 (4) ◽  
pp. 1588-1596 ◽  
Author(s):  
Sudipan Karmakar ◽  
Estrella A. Foster ◽  
Carolyn L. Smith
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Estrogen Receptor ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Small Interfering Rna ◽  
Breast Cancer Cells ◽  
Transcriptional Activity ◽  
Interfering Rna ◽  
Mcf 7

Each of the three members of the p160 steroid receptor coactivator (SRC) family of coactivators (SRC-1, SRC-2 and SRC-3) stimulates estrogen receptor (ER)-α function in trans-activation assays. Consequently, we sought to elucidate their contributions to the ER-regulated processes of cell proliferation, apoptosis, and the expression of ERα target genes in MCF-7 breast cancer cells. The small interfering RNA depletion of SRC-2 or SRC-3 but not SRC-1 inhibited growth of MCF-7 cells, and this was reflected in decreased cell cycle progression and increased apoptosis in SRC-2- or SRC-3-depleted cells as well as a reduction in ERα transcriptional activity measured on a synthetic reporter gene. However, only SRC-3 depletion blocked estradiol stimulated cell proliferation. Depletion of SRC-1 did not affect these events, and together this reveals functional differences between each of the three SRC family coactivators. Regulation of the endogenous ERα target gene, c-myc was not affected by depletion of any of the p160 coactivators although depletion of each of them decreased pS2 mRNA expression in estradiol-treated MCF-7 cells. Moreover, progesterone receptor and cyclin D1 gene expression were decreased in SRC-3 small interfering RNA-treated cells. Expression of mRNA and protein levels for the antiapoptotic gene, Bcl-2 was dependent on SRC-3 expression, whereas Bcl-2 protein but not mRNA expression also was sensitive to SRC-1 depletion. Together these data indicate that the closely related p160 coactivators are not functionally redundant in breast cancer cells because they play gene-specific roles in regulating mRNA and protein expression, and they therefore are likely to make unique contributions to breast tumorigenesis.

scholarly journals Biochanin A Promotes Proliferation that Involves a Feedback Loop of MicroRNA-375 and Estrogen Receptor Alpha in Breast Cancer Cells

2015 ◽  
Vol 35 (2) ◽  
pp. 639-646 ◽  
Author(s):  
Jian Chen ◽  
Bo Ge ◽  
Yong Wang ◽  
Yu Ye ◽  
Sien Zeng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Feedback Loop ◽  
Biochanin A ◽  
Mrna Levels ◽  
Mcf 7

Background: Biochanin A and formononetin are O-methylated isoflavones that are isolated from the root of Astragalus membranaceus, and have antitumorigenic effects. Our previous studies found that formononetin triggered growth-inhibitory and apoptotic activities in MCF-7 breast cancer cells. We performed in vivo and in vitro studies to further investigate the potential effect of biochanin A in promoting cell proliferation in estrogen receptor (ER)-positive cells, and to elucidate underlying mechanisms. Methods: ERα-positive breast cancer cells (T47D, MCF-7) were treated with biochanin A. The MTT assay and flow cytometry were used to assess cell proliferation and apoptosis. mRNA levels of ERα, Bcl-2, and miR-375 were quantified using real-time polymerase chain reaction. Compared with the control, low biochanin A concentrations (2-6 μM) stimulated ERα-positive cell proliferation (T47D, MCF-7). The more sensitive T47D cells were used to study the relevant signaling pathway. Results: After treatment with biochanin A, ERα, miR-375, and Bcl-2 expression was significantly upregulated. Additionally, in the in vivo studies, uterine weight in ovariectomized mice treated with biochanin A increased significantly. Conclusion: This study demonstrated that biochanin A promoted ERα-positive cell proliferation through miR-375 activation and this mechanism is possibly involving in a miR-375 and ERα feedback loop.

scholarly journals Effect of Estrogen on Heteronemin-Induced Anti-proliferative Effect in Breast Cancer Cells With Different Estrogen Receptor Status

2021 ◽  
Vol 9 ◽  
Author(s):  
Yu-Chen S. H. Yang ◽  
Zi-Lin Li ◽  
Tung-Yung Huang ◽  
Kuan-Wei Su ◽  
Chi-Yu Lin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Estrogen Receptor ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Gene Expressions ◽  
Er Positive ◽  
Mcf 7

Estrogen (E2) has multiple functions in breast cancers including stimulating cancer growth and interfering with chemotherapeutic efficacy. Heteronemin, a marine sesterterpenoid-type natural product, has cytotoxicity on cancer cells. Breast cancer cell lines, MCF-7 and MDA-MB-231, were used for investigating mechanisms involved in inhibitory effect of E2 on heteronemin-induced anti-proliferation in breast cancer cells with different estrogen receptor (ER) status. Cytotoxicity was detected by cell proliferation assay and flow cytometry, gene expressions were determined by qPCR, mechanisms were investigated by Western blot and Mitochondrial ROS assay. Heteronemin exhibited potent cytotoxic effects against both ER-positive and ER-negative breast cancer cells. E2 stimulated cell growth in ER-positive breast cancer cells. Heteronemin induced anti-proliferation via suppressing activation of ERK1/2 and STAT3. Heteronemin suppressed E2-induced proliferation in both breast cancer cells although some gene expressions and anti-proliferative effects were inhibited in the presence of E2 in MCF-7 and MDA-MB-231 cells with a higher concentration of heteronemin. Heteromenin decreased the Bcl-2/Bax ratio to inhibit proliferation in MDA-MB-231 but not in MCF-7 cells. Both heteronemin and E2 increased mitochondrial reactive oxygen species but combined treatment reversed superoxide dismutase (SOD)s accumulation in MCF-7 cells. Heteronemin caused G0/G1 phase arrest and reduced the percentage of cells in the S phase to suppress cancer cell growth. In conclusion, Heteronemin suppressed both ER-positive and ER-negative breast cancer cell proliferation. Interactions between E2 and heteronemin in signal transduction, gene expressions, and biological activities provide insights into the complex pathways by which anti-proliferation is induced by heteronemin in E2-replete environments.

Adaptive hypersensitivity to estrogen: mechanism for superiority of aromatase inhibitors over selective estrogen receptor modulators for breast cancer treatment and prevention.

2003 ◽  
pp. 111-130 ◽  
Author(s):  
R J Santen ◽  
R X Song ◽  
Z Zhang ◽  
R Kumar ◽  
M-H Jeng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Estrogen Receptor ◽  
Cell Membrane ◽  
Map Kinase ◽  
Aromatase Inhibitors ◽  
Morphological Changes ◽  
Biological Effects ◽  
Genomic Effects

Clinical observations suggest that human breast tumors can adapt to endocrine therapy by developing hypersensitivity to estradiol (E(2)). To understand the mechanisms responsible, we examined estrogenic stimulation of cell proliferation in a model system and provided in vitro and in vivo evidence that long-term E(2) deprivation (LTED) causes "adaptive hypersensitivity". The enhanced responses to E(2) do not involve mechanisms acting at the level of transcription of estrogen-regulated genes. We found no evidence of hypersensitivity when examining the effects of E(2) on regulation of c-myc, pS2, progesterone receptor, several estrogen receptor (ER) reporter genes, or c-myb in hypersensitive cells. Estrogen deprivation of breast cells long-term does up-regulate both the MAP kinase and phosphatidyl-inositol 3-kinase pathways. As a potential explanation for up-regulation of these signaling pathways, we found that ERalpha is 4- to 10-fold up-regulated and co-opts a classic growth factor pathway using Shc, Grb-2 and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. E(2) binds to cell membrane-associated ERalpha, physically associates with the adapter protein SHC, and induces its phosphorylation. In turn, Shc binds Grb-2 and Sos, which results in the rapid activation of MAP kinase. These non-genomic effects of E(2) produce biological effects as evidenced by Elk activation and by morphological changes in cell membranes. Further proof of the non-genomic effects of E(2) involved use of cells which selectively expressed ERalpha in the nucleus, cytosol and cell membrane. We created these COS-1 "designer cells" by transfecting ERalpha lacking a nuclear localization signal and containing a membrane localizing signal. The concept of "adaptive hypersensitivity" and the mechanisms responsible for this phenomenon have important clinical implications. Adaptive hypersensitivity would explain the superiority of aromatase inhibitors over the selective ER modulators (SERMs) for treatment of breast cancer. The development of highly potent third-generation aromatase inhibitors allows reduction of breast tissue E2 to very low levels and circumvents the enhanced sensitivity of these cells to the proliferative effects of E(2). Clinical trials in the adjuvant, neoadjuvant and advanced disease settings demonstrate the greater clinical efficacy of the aromatase inhibitors over the SERMs. More recent observations indicate that the aromatase inhibitors are superior for the prevention of breast cancer as well. These observations may be explained by the hypothesis that estrogens induce breast cancer both by stimulating cell proliferation and by their metabolism to genotoxic products. The SERMs block ER-mediated proliferation only, whereas the aromatase inhibitors exert dual effects on proliferation and genotoxic metabolite formation.

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