scholarly journals Oxysterol signalling is retained in ER-negative and supressed in ER-positive breast cancer

2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Samantha Hutchinson ◽  
Sebastiano Battaglia ◽  
Hanne Roberg-Larsen ◽  
Priscilia Lianto ◽  
Thomas Hughes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Tissue Bank ◽  
Disease Free Survival ◽  
Luciferase Reporter ◽  
Receptor Alpha ◽  
Increased Risk ◽  
Er Positive ◽  
Mcf 7 ◽  
Positive Breast Cancer

AbstractBreast cancer treatment and prognosis is informed by biomarker expression. Expression of Oestrogen Receptor-alpha (ERα) for example influences whether the patient receives endocrine- or chemo-therapy. Nutritional status is a modifier of disease free survival and elevated circulating cholesterol associates with increased risk of relapse. Cholesterol hydroxylation produces ‘oxysterols’ which are selective Liver X Receptor alpha (LXRα) modulators and ERα agonists. In ER-positive breast cancer, oxysterols induce proliferation and resistance to endocrine therapy, whilst in ER-negative disease oxysterols are anti-proliferative and pro-metastatic suggesting that there are breast cancer subtype specific differences in the genomic targets of the oxysterol-LXR pathway. This study explored the regulation of LXRα signalling in ER-positive and ER-negative breast cancer, and how ligand, receptor and co-factors combine to regulate LXRα target gene expression in different breast cancer types.In vitro, MDA.MB.468 (ER-negative) cells were more responsive than MCF-7 (ER-positive) cells to synthetic LXRα agonists (T0901317, GW3965) and six oxysterols (22-hydroxycholesterol [22-OHC], 24-OHC, 25-OHC, 27-OHC, 7-ketocholesterol and 24,25-epoxycholesterol), as measured by MTT, LXR-luciferase reporter, and qPCR of canonical targets ABCA1 and APOE (Students t-tests: p < 0.01). Responses to the antagonist GSK2033 was comparable across cell lines. In vivo, LXRa expression correlated with 48/146 target genes in ER-negative (n = 81), but with just 9/146 in ER-positive tumours (n = 234) (Fischer exact test: p < 0.0001) indicating greater LXRa-mediated transcription of target genes in the aggressive subtype. This was not explained by ligand concentration, as we developed a novel fast oxysterol detection system and found no difference in concentration of 22-OHC, 24-OHC, 25-OHC or 27-OHC between ER-negative (n = 11) and ER-positive (n = 11) primary tumours obtained from the Leeds Breast Tissue Bank. However, we did observe that expression of LXRa and 2/7 of its co-activators (SRC, TRRAP) were higher in ER-negative relative to ER-positive disease (using TCGA data from cBioPortal) (Mann-Whitney U test: p < 0.001), and that expression of all LXRa co-repressors were lowest in ER-negative disease (NCOR1, NCOR2, LCOR: Mann-Whitney U test: p < 0.001 for all). siRNA knock-down of NCOR1 and NCOR2 resulted in MCF-7 cells that mimicked the response of MDA.MB.468 cells to oxysterols (as measured by LXR-luciferase and qPCR assay).These data indicate that despite the anti-proliferative actions of oxysterol-LXRa signalling, there is a, yet to be identified, selective advantage for retention and enhancement of this pathway in ER-negative breast cancer. Dietary routes to selective LXRa modulation (such as plant sterols) may provide patient-led routes to improving ER-negative survival rates.

scholarly journals OCT1 Is a Poor Prognostic Factor for Breast Cancer Patients and Promotes Cell Proliferation via Inducing NCAPH

2021 ◽  
Vol 22 (21) ◽  
pp. 11505
Author(s):  
Takuya Ogura ◽  
Kotaro Azuma ◽  
Junichiro Sato ◽  
Keiichi Kinowaki ◽  
Ken-Ichi Takayama ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Prognostic Factor ◽  
Disease Free Survival ◽  
Breast Cancer Patients ◽  
Clinical Value ◽  
Poor Prognostic Factor ◽  
Er Positive ◽  
Mcf 7 ◽  
Positive Breast Cancer

Octamer transcription factor 1 (OCT1) is a transcriptional factor reported to be a poor prognostic factor in various cancers. However, the clinical value of OCT1 in breast cancer is not fully understood. In the present study, an immunohistochemical study of OCT1 protein was performed using estrogen receptor (ER)-positive breast cancer tissues from 108 patients. Positive OCT1 immunoreactivity (IR) was associated with the shorter disease-free survival (DFS) of patients (p = 0.019). Knockdown of OCT1 inhibited cell proliferation in MCF-7 breast cancer cells as well as its derivative long-term estrogen-deprived (LTED) cells. On the other hand, the overexpression of OCT1 promoted cell proliferation in MCF-7 cells. Using microarray analysis, we identified the non-structural maintenance of chromosomes condensin I complex subunit H (NCAPH) as a novel OCT1-taget gene in MCF-7 cells. Immunohistochemical analysis showed that NCAPH IR was significantly positively associated with OCT1 IR (p < 0.001) and that positive NCAPH IR was significantly related to the poor DFS rate of patients (p = 0.041). The knockdown of NCAPH inhibited cell proliferation in MCF-7 and LTED cells. These results demonstrate that OCT1 and its target gene NCAPH are poor prognostic factors and potential therapeutic targets for patients with ER-positive breast cancer.

scholarly journals Effect of Wnt5a on drug resistance in estrogen receptor-positive breast cancer

2020 ◽  
Author(s):  
Ai Amioka ◽  
Takayuki Kadoya ◽  
Satoshi Sueoka ◽  
Yoshie Kobayashi ◽  
Shinsuke Sasada ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Poor Prognosis ◽  
Breast Cancer Tissue ◽  
Cancer Tissue ◽  
Breast Cancer Patients ◽  
Mtor Signaling Pathway ◽  
The Poor ◽  
Er Positive ◽  
Mcf 7 ◽  
Positive Breast Cancer

Abstract BackgroundIt was previously reported by us that Wnt5a-positive breast cancer can be classified as estrogen receptor (ER)-positive breast cancer and its prognosis is worse than that of Wnt5a-negative breast cancer. Herein, the molecular mechanisms underlying the poor prognosis of Wnt5a-positive breast cancer patients were examined. MethodsA total of 151 consecutive ER-positive breast cancer patients who underwent resection between January 2011 and February 2014 were enrolled. DNA microarray and pathway analyses were performed conducted using MCF-7 cells stably expressing Wnt5a (MCF-7/Wnt5a(+)). Based on the results, cell viability and drug sensitivity assays as well as mutation analysis , were performed using culture cells and breast cancer tissue. The relationship between Wnt5a and the PI3K–AKT–mTOR signaling pathway was examined.ResultsThe relapse-free survival rate in patients with Wnt5a-positive breast cancer was significantly lower than that in patients with Wnt5a-negative breast cancer ( P = 0.047). DNA microarray data indicated that only the cytochrome P450 (CYP) pathway was significantly upregulated in MCF-7/Wnt5a(+) cells ( P = 0.0440). MCF-7/Wnt5a(+) cells showed reduced sensitivity to the metabolic substrates of CYP, tamoxifen ( P < 0.001), and paclitaxel ( P < 0.001). PIK3CA mutations were unrelated to Wnt5a expression in breast cancer tissue and culture cells.ConclusionsIn ER-positive breast cancer, Wnt5a upregulated the CYP metabolic pathway; additionally, it inhibited the sensitivity to tamoxifen and paclitaxel, which constitute the standard treatment options for ER-positive breast cancer. Wnt5a could be involved in the poor prognosis of ER-positive breast cancer independently of the PI3K–AKT–mTOR signaling pathway.

Effectiveness of adjuvant chemotherapy in combination with tamoxifen for node-positive postmenopausal breast cancer patients.

1997 ◽  
Vol 15 (4) ◽  
pp. 1385-1394 ◽  
Author(s):  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Disease Free Survival ◽  
Postmenopausal Breast Cancer ◽  
Breast Cancer Patients ◽  
Node Positive ◽  
Increased Risk ◽  
Node Positive Disease ◽  
Er Positive ◽  
Risk Of Relapse

PURPOSE Adjuvant tamoxifen has been shown to reduce relapse and mortality among node-positive post-menopausal breast cancer patients. The value of adding chemotherapy to tamoxifen is controversial. PATIENTS AND METHODS Between July 1986 and April 1993, 1,266 postmenopausal breast cancer patients with node-positive disease were randomly assigned to receive one of four adjuvant therapy regimens: (A) tamoxifen alone for 5 years; (B) tamoxifen plus three courses of early cyclophosphamide, methotrexate, and fluorouracil (CMF) on months 1, 2, and 3; (C) tamoxifen plus delayed single courses of CMF on months 9, 12, and 15; (D) tamoxifen plus early and delayed CMF on months 1, 2, 3, 9, 12, and 15. The two-by-two factorial design allowed two direct comparisons: early CMF (B and D) versus no early CMF (A and C), and delayed CMF (C and D) versus no delayed CMF (A and B). Estrogen receptor (ER) status was known for all patients and was used to stratify the randomization. A total of 1, 212 patients (96%) were eligible and assessable. The median follow-up duration was 60 months. RESULTS The results of the two-by-two factorial comparisons were as follows: (1) early CMF added to tamoxifen significantly improved 5-year disease-free survival (DFS; 64% v 57%; hazards ratio [HR], 0.79; 95% confidence interval [CI], 0.66 to 0.95; P = .01); and (2) delayed CMF added to tamoxifen did not improve DFS (5-year DFS, 61% v 60%; HR, 0.97; 95% CI, 0.81 to 1.17; P = .77). For patients with ER-positive tumors, the addition of CMF, either early or delayed or both, reduced the relative risk of relapse by 22% to 36%. In contrast, for patients with ER-negative tumors, tamoxifen with delayed CMF was associated with a nonsignificant increased risk of relapse (HR, 1.27; 95% CI, 0.92 to 1.76; P = .15). CONCLUSION Postmenopausal patients with node-positive breast cancer should be offered combination chemotherapy in addition to tamoxifen. Tamoxifen should not be initiated before CMF, as this might be detrimental, especially for patients with ER-negative tumors.

scholarly journals SGK3 Is an Estrogen-Inducible Kinase Promoting Estrogen-Mediated Survival of Breast Cancer Cells

2011 ◽  
Vol 25 (1) ◽  
pp. 72-82 ◽  
Author(s):  
Yuanzhong Wang ◽  
Dujin Zhou ◽  
Sheryl Phung ◽  
Selma Masri ◽  
David Smith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Kinase ◽  
Cell Survival ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Dependent Manner ◽  
Binding Regions ◽  
Er Positive ◽  
Mcf 7 ◽  
Positive Breast Cancer

Serum- and glucocorticoid-inducible kinase 3 (SGK3) is a protein kinase of the AGC family of protein kinase A, protein kinase G, and protein kinase C and functions downstream of phosphatidylinositol 3-kinase (PI3K). Recent study revealed that SGK3 plays a pivotal role in Akt/protein kinase B independent signaling downstream of oncogenic PI3KCA mutations in breast cancer. Here we report that SGK3 is an estrogen receptor (ER) transcriptional target and promotes estrogen-mediated cell survival of ER-positive breast cancer cells. Through a meta-analysis on 22 microarray studies of breast cancer in the Oncomine database, we found that the expression of SGK3 is significantly higher (5.7-fold, P &lt; 0.001) in ER-positive tumors than in ER-negative tumors. In ER-positive breast cancer cells, SGK3 expression was found to be induced by 17β-estradiol (E2) in a dose- and time-dependent manner, and the induction of SGK3 mRNA by E2 is independent of newly synthesized proteins. We identified two ERα-binding regions at the sgk3 locus through chromatin immunoprecipitation with massively parallel DNA sequencing. Promoter analysis revealed that ERα stimulates the activity of sgk3 promoters by interaction with these two ERα-binding regions on E2 treatment. Loss-of-function analysis indicated that SGK3 is required for E2-mediated cell survival of MCF-7 breast carcinoma cells. Moreover, overexpression of SGK3 could partially protect MCF-7 cells against apoptosis caused by antiestrogen ICI 182,780. Together, our study defines the molecular mechanism of regulation of SGK3 by estrogen/ER and provides a new link between the PI3K pathway and ER signaling as well as a new estrogen-mediated cell survival mechanism mediated by SGK3 in breast cancer cells.

scholarly journals 17β-estradiol-containing liposomes as a novel delivery system for the antisense therapy of ER-positive breast cancer: An in vitro study on the MCF-7 cell line

2014 ◽  
Vol 33 (2) ◽  
pp. 921-929 ◽  
Author(s):  
ZBYNEK HEGER ◽  
JAROMIR GUMULEC ◽  
NATALIA CERNEI ◽  
KATERINA TMEJOVA ◽  
PAVEL KOPEL ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Delivery System ◽  
In Vitro Study ◽  
Antisense Therapy ◽  
Er Positive ◽  
17Β Estradiol ◽  
Mcf 7 ◽  
Positive Breast Cancer

scholarly journals ER-Negative Breast Cancer Is Highly Responsive to Cholesterol Metabolite Signalling

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2618 ◽  
Author(s):  
Samantha A Hutchinson ◽  
Priscilia Lianto ◽  
Hanne Roberg-Larsen ◽  
Sebastiano Battaglia ◽  
Thomas A Hughes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Target Genes ◽  
Cholesterol Metabolism ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Cancer Subtypes ◽  
Hormone Receptor Positive ◽  
Er Positive ◽  
Positive Breast Cancer

Interventions that alter cholesterol have differential impacts on hormone receptor positive- and negative-breast cancer risk and prognosis. This implies differential regulation or response to cholesterol within different breast cancer subtypes. We evaluated differences in side-chain hydroxycholesterol and liver X nuclear receptor signalling between Oestrogen Receptor (ER)-positive and ER-negative breast cancers and cell lines. Cell line models of ER-positive and ER-negative disease were treated with Liver X Receptor (LXR) ligands and transcriptional activity assessed using luciferase reporters, qPCR and MTT. Publicly available datasets were mined to identify differences between ER-negative and ER-positive tumours and siRNA was used to suppress candidate regulators. Compared to ER-positive breast cancer, ER-negative breast cancer cells were highly responsive to LXR agonists. In primary disease and cell lines LXRA expression was strongly correlated with its target genes in ER-negative but not ER-positive disease. Expression of LXR’s corepressors (NCOR1, NCOR2 and LCOR) was significantly higher in ER-positive disease relative to ER-negative, and their knock-down equalized sensitivity to ligand between subtypes in reporter, gene expression and viability assays. Our data support further evaluation of dietary and pharmacological targeting of cholesterol metabolism as an adjunct to existing therapies for ER-negative and ER-positive breast cancer patients.

Identification of estrogenically synthesized LRP16 as an ERα coactivator and its role in ERα-positive breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10676-10676
Author(s):  
W. Han ◽  
Y. Zhao ◽  
Z. Wu ◽  
Y. Mu ◽  
L. Yu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Northern Blot ◽  
Breast Cancer Cells ◽  
Tumor Diameter ◽  
Er Positive ◽  
Mcf 7 ◽  
Positive Breast Cancer

10676 Background: Aberrant ERα activity is linked to genesis and malignant progression of breast cancer through direct target gene activation or repression. A complex network of coregulatory proteins is largely believed to determine the transcriptional activity of ERα. LRP16 was identified previously to be an estrogen (E2) responsive gene, but its function involving in conferring estrogen signalling pathway is not clear. Methods: Endogenous LRP16 expression in MCF-7 cells was stably suppressed by retrovirus-mediated small interference RNA (siRNA). The effects of LRP16 expression on E2-stimulated growth and invasive ability of MCF-7 cells were determined in vitro and in vivo assays. The effects of LRP16 expression on ERα transactivation were determined by luciferase assays. The interaction of LRP16 and ERα was examined by GST pull-down and coimmunopricipitation (CoIP) assays. Northern blot and Western blot were used to detect the mRNA and protein levels of ER target genes in LRP16-inhibited MCF-7 cells. The LRP16 expression levels in primary breast cancer were detected by Northern blot. Results: Fristly, LRP16 expression was characterized to be dependent on estrogen activities. Then, LRP16 was identified to be an estrogen-independent ERα cofactor in ER-positive breast cancer cells and demonstrate that LRP16 is an essential coactivator to ERα-mediated transactivation in an estrogen-dependent manner. Suppression of LRP16 expression in ER-positive breast cancer cells specifically inhibits the transcription of ER upregulated genes, results in the increase of E-cadherin expression through ER mediation. In vitro and in vivo data demonstrate that suppression of LRP16 inhibits the ability of estrogen-stimulated proliferation and invasiveness of ER-positive breast cancer cells. The pathological and clinical characteristics of human breast cancer includining ER/PR-positiveness, tumor diameter and the involvement of axillary lymphoid nodes were tightly linked with the LRP16 gene expression level. Conclusions: These results establish a mechanistic link between estrogen receptor status, its coactivator LRP16, and progression of ER-positive breast cancers, and may provide a novel antiestrogenic target for the therapy of ER positive breast cancer. No significant financial relationships to disclose.

scholarly journals miR-520h Stimulates Drug Resistance to Paclitaxel by Targeting the OTUD3-PTEN Axis in Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Wenwen Geng ◽  
Haiyun Song ◽  
Qianqian Zhao ◽  
Ke Dong ◽  
Qian Pu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Ectopic Expression ◽  
Cancer Cell Line ◽  
Luciferase Reporter ◽  
Paclitaxel Resistance ◽  
Exact Function ◽  
Mcf 7

MicroRNAs (miRNAs) have been identified as negative posttranscriptional regulators of target genes and are involved directly in the pathological processes of tumors, including drug resistance. However, the exact function of miR-520h in breast cancer remains poorly understood. The aim of this study was to investigate the molecular mechanisms of miR-520h in paclitaxel resistance in the MCF-7 breast cancer cell line. Ectopic expression of miR-520h could promote the proliferation of breast cancer cells and inhibit paclitaxel-induced cell apoptosis. Inhibiting the expression of miR-520h could enhance the sensitivity to paclitaxel in paclitaxel-resistant MCF-7/Taxol cells. Furthermore, luciferase reporter assays showed that OTUD3 was a direct target of miR-520h. OTUD3 plays a necessary role in the paclitaxel resistance effect of miR-520h, and cotreatment with a miR-520h inhibitor and OTUD3 overexpression significantly enhanced MCF-7 cell sensitivity to paclitaxel. Moreover, miR-520h substantially inhibited the protein expression of PTEN via OTUD3 and subsequently affected downstream p-AKT pathway activity. In a clinical study, we also found that high miR-520h expression was associated with more aggressive pathological characteristic and poor prognosis. Therefore, our findings showed that miR-520h targeted the OTUD3-PTEN axis to drive paclitaxel resistance, and this miR might be an important potential target for breast cancer treatment.

HER2 FISH ratio cut-points and pathologic complete response (pCR), residual tumor (RT), HER2 status, and survival prediction in HER2-positive breast cancer (BC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22033-e22033
Author(s):  
R. S. Mehta ◽  
D. Jackson ◽  
T. Schubbert ◽  
D. Hsiang
Keyword(s):  
Breast Cancer ◽  
Pathologic Complete Response ◽  
Endocrine Resistance ◽  
Disease Free Survival ◽  
Survival Prediction ◽  
Her2 Positive ◽  
Cut Point ◽  
Her2 Positive Breast Cancer ◽  
Er Positive ◽  
Positive Breast Cancer

e22033 Background: We demonstrated that pCR is correlated with increasing HER2-FISH ratio, while disease-free survival (DFS) with pCR and ER-positivity in HER2-positive breast cancer treated with trastuzumab (SABCS 2008). It is known that quantitative HER2-FISH ratio correlates with ER levels and HER2-positivity imparts a higher grade in ER-positive BC. Collectively, we hypothesized that combined ER (≥10) and a HER2 ratio cut-point may subdivide HER2-positive BC into pCR predictive subtypes.Methods: Of the 80 HER2-positive (IHC3+/FISH+) BC, quantitative HER2 FISH ratio (widely spread over 1–18.3) and ER correlation was noted (r=0.34, p=0.002). Moreover, HER2 ratio (>4) correlated with higher Ki-67 (r= 0.5, p=0.01) and grade (p trend=0.05) in ER-positive subtype, inferring a biologic cut-point. Results: Of patients with stage I-IV BC treated neoadjuvantly (92% trastuzumab-based), pCR was 0% (0/13) in ER-positive-low-HER2 compared to 77% (10/13, p=0.0001), 75% (24/32, p<0.0001) and 37.5% (3/8, p=0.043) in ER-positive-high-HER2, ER-negative-high-HER2 and ER-negative-low-HER2, respectively. DFS was 100, 90, 80% and 60% (logrank-trend p<0.05) in these 4 subtypes (excluding stage IV), respectively, at a median follow-up of 38 months (range 6–72). In ER-negative subtypes, DFS was 97% and 29% (logrank p=0.0001) in patients with or without pCR; of the six with RT, 0% DFS was noted in four with HER2-negative/HER2-reduced (HER2-R) RT, compared to 100% in the two with unchanged HER2 (p=<0.05, logrank test). In ER-positive subtypes, DFS is 95% overall, and 100% in patients with RT; 7 of 10 tested RT were HER2- R. Conclusions: pCR is crucial and high in ER-negative-high-HER2 and is crucial (but low) in ER-negative-low-HER2-positive BC for improved outcome. Improved DFS is associated with high pCR in ER-positive-high-HER2 BC, but is independent of the low pCR in ER-positive-low-HER2-subtype. Thus, combined HER2 and ER offer improved prediction. In hypothesis generating analysis, HER2-R may underlie relapse in ER-negative subtypes (HER2-basal-transitional-residual), while it may be beneficial in ER-positive subtypes (luminal-B- A-transitional) by reducing HER2-pathway mediated endocrine resistance. [Table: see text]

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