oestrogen receptor
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PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262360
Author(s):  
Mathias Rass ◽  
Laura Gizler ◽  
Florian Bayersdorfer ◽  
Christoph Irlbeck ◽  
Matthias Schramm ◽  
...  

Over the years Ski and Sno have been found to be involved in cancer progression e.g. in oesophageal squamous cell carcinoma, melanoma, oestrogen receptor-positive breast carcinoma, colorectal carcinoma, and leukaemia. Often, their prooncogenic features have been linked to their ability of inhibiting the anti-proliferative action of TGF-ß signalling. Recently, not only pro-oncogenic but also anti-oncogenic functions of Ski/Sno proteins have been revealed. Besides Ski and Sno, which are ubiquitously expressed other members of Ski/Sno proteins exist which show highly specific neuronal expression, the SKI Family Transcriptional Corepressors (Skor). Among others Skor1 and Skor2 are involved in the development of Purkinje neurons and a mutation of Skor1 has been found to be associated with restless legs syndrome. But neither Skor1 nor Skor2 have been reported to be involved in cancer progression. Using overexpression studies in the Drosophila eye imaginal disc, we analysed if the Drosophila Skor homologue Fuss has retained the potential to inhibit differentiation and induce increased proliferation. Fuss expressed in cells posterior to the morphogenetic furrow, impairs photoreceptor axon pathfinding and inhibits differentiation of accessory cells. However, if its expression is induced prior to eye differentiation, Fuss might inhibit the differentiating function of Dpp signalling and might maintain proliferative action of Wg signalling, which is reminiscent of the Ski/Sno protein function in cancer.


2022 ◽  
pp. e000335
Author(s):  
Isabelle Romieu ◽  
Neha Khandpur ◽  
Aikaterini Katsikari ◽  
Carine Biessy ◽  
Gabriela Torres-Mejía ◽  
...  

Ultra-processed food intake has been linked to an increased risk of breast cancer in Western populations. No data are available in the Latin American population although the consumption of ultra-processed foods is increasing rapidly in this region.We evaluated the association of ultra-processed food intake to breast cancer risk in a case–control study including 525 cases (women aged 20–45 years) and 525 matched population-based controls from Chile, Colombia, Costa Rica and Mexico. The degree of processing of foods was classified according to the NOVA classification.Overall, the major contributors to ultra-processed food intake were ready-to-eat/heat foods (18.2%), cakes and desserts (16.7%), carbonated and industrial fruit juice beverages (16.7%), breakfast cereals (12.9%), sausages and reconstituted meat products (12.1%), industrial bread (6.1%), dairy products and derivatives (7.6%) and package savoury snacks (6.1%). Ultra-processed food intake was positively associated with the risk of breast cancer in adjusted models (OR T3-T1=1.93; 95% CI=1.11 to 3.35). Specifically, a higher risk was observed with oestrogen receptor positive breast cancer (ORT3-T1=2.44, (95% CI=1.01 to 5.90, P-trend=0.049), while no significant association was observed with oestrogen receptor negative breast cancer (ORT3-T1=1.87, 95% CI=0.43 to 8.13, P-trend=0.36).Our findings suggest that the consumption of ultra-processed foods might increase the risk of breast cancer in young women in Latin America. Further studies should confirm these findings and disentangle specific mechanisms relating ultra-processed food intake and carcinogenic processes in the breast.


2022 ◽  
Vol 3 (1) ◽  
pp. e54-e66
Author(s):  
Neil Carleton ◽  
Azadeh Nasrazadani ◽  
Kristine Gade ◽  
Sushil Beriwal ◽  
Parul N Barry ◽  
...  

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 94
Author(s):  
Reham M. Mashat ◽  
Hanna A. Zielinska ◽  
Jeff M. P. Holly ◽  
Claire M. Perks

Cholesterol—in particular, high levels of low-density lipoprotein (LDL) and its metabolite, 27-hydroxycholesterol (27-OHC)—is correlated with increases in the risks of breast cancer and obesity. Although the high expression of LDL/27-OHC has been reported in breast cancer, its effects and mechanism of action remain to be fully elucidated. In this study, we found that the effects of LDL on cell proliferation were mediated by the activation of the cytochrome P450 enzyme, sterol 27 hydroxylase, and cholesterol 27-hydroxylase (CYP27A1) in both ER-α-positive and ER-α-negative breast cancer cells. We found that treatment with 27-OHC only increased cell growth in oestrogen receptor-α (ER-α)-positive breast cancer cells in an ER-α-dependent manner, but, interestingly, the effects of 27-OHC on cell migration and invasion were independent of ER-α. Using ER-α-negative MDA-MB-231 cells, we found that 27-OHC similarly promoted cell invasion and migration, and this was mediated by oestrogen receptor β (ER-β). These results suggest that 27-OHC promotes breast cancer cell proliferation in ER-α-positive breast cancer cells via ER-α, but migration and invasion are mediated via ER-β in ER-α positive and negative cell lines. The addition of LDL/27OHC increased the production of IGF-I and the abundance of IGF-IR in TNBC. We further found that modulating ER-β using an agonist or antagonist increased or decreased, respectively, levels of the IGF-I and EGF receptors in TNBC. The inhibition of the insulin-like growth factor receptor blocked the effects of cholesterol on cell growth and the migration of TNBC. Using TCGA and METABRIC microarray expression data from invasive breast cancer carcinomas, we also observed that higher levels of ER-beta were associated with higher levels of IGF-IR. Thus, this study shows novel evidence that ER-β is central to the effects of LDL/27OHC on invasion, migration, and the IGF and EGF axes. Our data suggest that targeting ER-β in TNBC could be an alternative approach for downregulating IGF/EGF signalling and controlling the impact of LDL in breast cancer patients.


Oncogene ◽  
2021 ◽  
Author(s):  
Rebecca Williams ◽  
Stephanie Jobling ◽  
Andrew H. Sims ◽  
Chunyan Mou ◽  
Lorna Wilkinson ◽  
...  

AbstractEctodysplasin A receptor (EDAR) is a death receptor in the Tumour Necrosis Factor Receptor (TNFR) superfamily with roles in the development of hair follicles, teeth and cutaneous glands. Here we report that human Oestrogen Receptor (ER) negative breast carcinomas which display squamous differentiation express EDAR strongly. Using a mouse model with a high Edar copy number, we show that elevated EDAR signalling results in a high incidence of mammary tumours in breeding female mice. These tumours resemble the EDAR-high human tumours in that they are characterised by a lack of oestrogen receptor expression, contain extensive squamous metaplasia, and display strong β-catenin transcriptional activity. In the mouse model, all of the tumours carry somatic deletions of the third exon of the CTNNB1 gene that encodes β-catenin. Deletion of this exon yields unconstrained β-catenin signalling activity. We also demonstrate that β-catenin activity is required for transformed cell growth, showing that increased EDAR signalling creates an environment in which β-catenin activity can readily promote tumourigenesis. Together, this work identifies a novel death receptor oncogene in breast cancer, whose mechanism of transformation is based on the interaction between the WNT and Ectodysplasin A (EDA) pathways.


2021 ◽  
Vol 12 ◽  
Author(s):  
Carla Miranda ◽  
Macarena Galleguillos ◽  
Roberto Torres ◽  
Karla Tardón ◽  
Dante D. Cáceres ◽  
...  

Tamoxifen (TAM), a selective oestrogen receptor modulator, is one of the most used treatments in oestrogen receptor-positive (ER+) early and metastatic breast cancer (BC) patients. The response to TAM has a high degree of inter-individual variability. This is mainly due to genetic variants in CYP2D6 gene, as well as other genes encoding proteins involved in the TAM pharmacokinetic and/or pharmacodynamic. Therefore, prediction of the TAM response using these genetic factors together with other non-genetic variables may be relevant to improve breast cancer treatment. Thus, in this work, we used genetic polymorphisms and clinical variables for TAM response modelling. One hundred sixty-two ER + BC patients with 2 years of TAM treatment were retrospectively recruited, and the genetic polymorphisms CYP2D6*4, CYP3A4*1B (CYP3A4*1.001), CYP3A5*3, UGT2B7*2, UGT2B15*2, SULT1A1*2, and ESRA V364E were analyzed by PCR-RFLP. Concomitantly, the therapeutic response was obtained from clinical records for association with genotypes using univariate and multivariate biostatistical models. Our results show that UGT2B15*1/*2 genotype protects against relapse (OR = 0.09; p = 0.02), CYP3A5*3/*3 genotype avoids endometrial hyperplasia (OR = 0.07; p = 0.01), SULT1A1*1/*2 genotype avoids vaginal bleeding (OR = 0.09; p = 0.03) and ESRA 364E/364E genotype increases the probability of vaginal bleeding (OR = 5.68; p = 0.02). Logistic regression models, including genomic and non-genomic variables, allowed us to obtain preliminary predictive models to explain relapse (p = 0.010), endometrial hyperplasia (p = 0.002) and vaginal bleeding (p = 0.014). Our results suggest that the response to TAM treatment in ER + BC patients might be associated with the presence of the studied genetic variants in UGT2B15, CYP3A5, SULT1A1 and ESRA genes. After clinical validation protocols, these models might be used to help to predict a percentage of BC relapse and adverse reactions, improving the individual response to TAM-based treatment.


2021 ◽  
Author(s):  
◽  
Catherine Elizabeth Judith Davis

<p>Kākāpō (Strigops habroptilus) are a critically endangered parrot species endemic to New Zealand that exhibit a reproductive strategy linked to “masting” years. Crucial to their survival is increased reproductive success. It has been hypothesised that their pattern of reproduction is synchronised with a steroidal “trigger” present in plants during intensive masting. If this hypothesis is valid, then Kākāpō and other closely related NZ parrots might be receptive to these masting plants in a manner different from that of other avian species.  The aims of this study were firstly, to identify whether unique amino acid motifs were present in the ligand binding domains (LBD) for the steroid receptors oestrogen receptor α (ER-α), oestrogen receptor β (ER-β), androgen receptor (AR) and progesterone receptor (PR) for the New Zealand parrots Kākāpō, Kākā, Kākāriki and Kea. These LBD amino acid sequences were compared with those in an Australian parrot, the Cockatiel, as well as in Chicken and Japanese Quail. Moreover, the role of these amino acid changes on the binding of ligands (both the native ligand and other steroidogenic compounds) for ER-α was assessed by in silico modelling by comparing the most favourable binding position of the ligands in the three-dimensional structure of Kākāpō ER-α with that of human ER-α. The second aim was to test extracts of New Zealand native plants known to be a food source for Kākāpō for their seasonal variation in oestrogenic activity and hence possible involvement in the reproductive cycle of Kākāpō.  The LBD for ER-β and AR of the parrot species (New Zealand and Australian) displayed 100% identity whilst those for ER-α and PR had variations. When the parrot sequences were compared with those for other avian species and human, there were a number of amino acid differences present, with the greatest disparity present in the LBD of ER-α. From in silico modelling studies, the amino acid substitutions in this receptor were predicted to have an indirect influence on the binding position of both 17β-oestradiol and a number of phytoestrogens through changes in the structure of this region. Consequently, this could have an effect on the binding affinity of certain plant chemicals for ER-α and thus their potency.  Plants extracts from the foliage and fruit of native New Zealand species were screened for oestrogenic activity in a yeast bioassay transfected with the human isoform of ER-α. The results from these experiments indicated that all the plants tested (excluding Dacrycarpus dacrydioides) exhibited detectable oestrogenic activity and a number also displayed variable and sometimes seasonal trends in activity.  In summary, the results in this study identified ER-α LBD amino acid motifs unique to New Zealand parrots. For the other steroid receptors, the ER-β LBD had a three amino acid combination of M, V and L that was only present in the parrot species whilst both the AR and PR LBD displayed much greater inter-species conservation. These changes, particularly those in the ER-α LBD, may influence the binding of steroidogenic compounds, known to be present in the plants consumed by Kākāpō as demonstrated by in silico modelling. Thus, this research provides evidence that the diet of Kākāpō may influence their reproductive pattern. However, it remains to be determined whether the steroidogenic potency of these plant extracts is modified when interacting with the unique LBD of native NZ parrots.</p>


2021 ◽  
Author(s):  
◽  
Catherine Elizabeth Judith Davis

<p>Kākāpō (Strigops habroptilus) are a critically endangered parrot species endemic to New Zealand that exhibit a reproductive strategy linked to “masting” years. Crucial to their survival is increased reproductive success. It has been hypothesised that their pattern of reproduction is synchronised with a steroidal “trigger” present in plants during intensive masting. If this hypothesis is valid, then Kākāpō and other closely related NZ parrots might be receptive to these masting plants in a manner different from that of other avian species.  The aims of this study were firstly, to identify whether unique amino acid motifs were present in the ligand binding domains (LBD) for the steroid receptors oestrogen receptor α (ER-α), oestrogen receptor β (ER-β), androgen receptor (AR) and progesterone receptor (PR) for the New Zealand parrots Kākāpō, Kākā, Kākāriki and Kea. These LBD amino acid sequences were compared with those in an Australian parrot, the Cockatiel, as well as in Chicken and Japanese Quail. Moreover, the role of these amino acid changes on the binding of ligands (both the native ligand and other steroidogenic compounds) for ER-α was assessed by in silico modelling by comparing the most favourable binding position of the ligands in the three-dimensional structure of Kākāpō ER-α with that of human ER-α. The second aim was to test extracts of New Zealand native plants known to be a food source for Kākāpō for their seasonal variation in oestrogenic activity and hence possible involvement in the reproductive cycle of Kākāpō.  The LBD for ER-β and AR of the parrot species (New Zealand and Australian) displayed 100% identity whilst those for ER-α and PR had variations. When the parrot sequences were compared with those for other avian species and human, there were a number of amino acid differences present, with the greatest disparity present in the LBD of ER-α. From in silico modelling studies, the amino acid substitutions in this receptor were predicted to have an indirect influence on the binding position of both 17β-oestradiol and a number of phytoestrogens through changes in the structure of this region. Consequently, this could have an effect on the binding affinity of certain plant chemicals for ER-α and thus their potency.  Plants extracts from the foliage and fruit of native New Zealand species were screened for oestrogenic activity in a yeast bioassay transfected with the human isoform of ER-α. The results from these experiments indicated that all the plants tested (excluding Dacrycarpus dacrydioides) exhibited detectable oestrogenic activity and a number also displayed variable and sometimes seasonal trends in activity.  In summary, the results in this study identified ER-α LBD amino acid motifs unique to New Zealand parrots. For the other steroid receptors, the ER-β LBD had a three amino acid combination of M, V and L that was only present in the parrot species whilst both the AR and PR LBD displayed much greater inter-species conservation. These changes, particularly those in the ER-α LBD, may influence the binding of steroidogenic compounds, known to be present in the plants consumed by Kākāpō as demonstrated by in silico modelling. Thus, this research provides evidence that the diet of Kākāpō may influence their reproductive pattern. However, it remains to be determined whether the steroidogenic potency of these plant extracts is modified when interacting with the unique LBD of native NZ parrots.</p>


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