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

Breast Cancer ◽  
2021 ◽  
Author(s):  
Ai Amioka ◽  
Takayuki Kadoya ◽  
Satoshi Sueoka ◽  
Yoshie Kobayashi ◽  
Shinsuke Sasada ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Patients ◽  
Poor Prognosis ◽  
Breast Cancer Patients ◽  
Mtor Signaling Pathway ◽  
The Poor ◽  
Er Positive ◽  
Mcf 7 ◽  
Positive Breast Cancer

Abstract Background Previously, we reported that Wnt5a-positive breast cancer can be classified as estrogen receptor (ER)-positive breast cancer; its prognosis is worse than that of Wnt5a-negative breast cancer. This study aimed to investigate the mechanisms underlying the poor prognosis in Wnt5a-positive breast cancer patients. Methods In total, 151 consecutive ER-positive breast cancer patients who underwent resection between January 2011 and February 2014 were enrolled. DNA microarray and pathway analyses were conducted using MCF-7 cells stably expressing Wnt5a [MCF-7/Wnt5a (+)]. Based on the outcomes, cell viability/drug sensitivity assays, and mutation analysis were performed using cell cultures and breast cancer tissues. The relationship between Wnt5a and the PI3K–AKT–mTOR signaling pathway was also examined. Results The 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 suggest that only the cytochrome P450 (CYP) pathway was significantly upregulated in MCF-7/Wnt5a (+) cells (P = 0.0440). Additionally, MCF-7/Wnt5a (+) cells displayed reduced sensitivity to the metabolic substrates of CYP, tamoxifen (P < 0.001), paclitaxel (P < 0.001), and cyclophosphamide (P < 0.001). Of note, PIK3CA mutations were not associated with the expression of Wnt5a in breast cancer tissue and culture cells. Conclusions In ER-positive breast cancer, Wnt5a upregulates the CYP metabolic pathway and suppresses tamoxifen, paclitaxel, and cyclophosphamide resistance, all of the three, standard treatment methods for ER-positive breast cancer. Wnt5a is thus potentially involved in the poor prognosis of ER-positive breast cancer independently of the PI3K–AKT–mTOR signaling pathway.

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.

scholarly journals ESR1-Stabilizing Long Noncoding RNA TMPO-AS1 Promotes Hormone-Refractory Breast Cancer Progression

2019 ◽  
Vol 39 (23) ◽  
Author(s):  
Yuichi Mitobe ◽  
Kazuhiro Ikeda ◽  
Takashi Suzuki ◽  
Kiyoshi Takagi ◽  
Hidetaka Kawabata ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Cancer Progression ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Breast Cancer Patients ◽  
Er Positive ◽  
Positive Breast Cancer

ABSTRACT Acquired endocrine therapy resistance is a significant clinical problem for breast cancer patients. In recent years, increasing attention has been paid to long noncoding RNA (lncRNA) as a critical modulator for cancer progression. Based on RNA-sequencing data of breast invasive carcinomas in The Cancer Genome Atlas database, we identified thymopoietin antisense transcript 1 (TMPO-AS1) as a functional lncRNA that significantly correlates with proliferative biomarkers. TMPO-AS1 positivity analyzed by in situ hybridization significantly correlates with poor prognosis of breast cancer patients. TMPO-AS1 expression was upregulated in endocrine therapy-resistant MCF-7 cells compared with levels in parental cells and was estrogen inducible. Gain and loss of TMPO-AS1 experiments showed that TMPO-AS1 promotes the proliferation and viability of estrogen receptor (ER)-positive breast cancer cells in vitro and in vivo. Global expression analysis using a microarray demonstrated that TMPO-AS1 is closely associated with the estrogen signaling pathway. TMPO-AS1 could positively regulate estrogen receptor 1 (ESR1) mRNA expression by stabilizing ESR1 mRNA through interaction with ESR1 mRNA. Enhanced expression of ESR1 mRNA by TMPO-AS1 could play a critical role in the proliferation of ER-positive breast cancer. Our findings provide a new insight into the understanding of molecular mechanisms underlying hormone-dependent breast cancer progression and endocrine resistance.

Translational cell study exploring the role of estrogen receptor β expression as a predictive and/or prognostic factor in breast cancer patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22185-e22185
Author(s):  
S. Saji ◽  
N. Honma ◽  
M. Hirose ◽  
S. Hayashi ◽  
K. Kuroi
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cell Line ◽  
Cancer Patients ◽  
Triple Negative ◽  
Breast Cancer Patients ◽  
Her 2 ◽  
Mcf 7 ◽  
Cell Study ◽  
Positive Breast Cancer

e22185 Background: We have reported that positive expression of Estrogen receptor β (ERβ) was associated with better prognosis in the early breast cancer patients treated with adjuvant tamoxifen monotherapy (J Clin Oncol. 2008). In addition, this was also true in the ERα-negative/PR-negative/Her-2 negative patients. We explored the biological impact of ERβ in breast cancer cell lines to determine whether these observations were due to its prognostic power or predictive power of response to the therapy. Methods: Since MCF-7 cell was ERβ-negative ERα-positive cell line, we established two stable clones of MCF-7 by introducing ERβ expression vector (β-clone 1, β-clone 2) as the model of ERβ-positive ERα-positive breast cancer. MDA-MB 231 cell was used as ERβ-positive triple-negative cell line. These cells were subjected to proliferation, expression and functional analysis. Results: In western blotting, both β-clone 1 and clone 2 showed decreased expression of PR and Her-2 than parent MCF-7, although there were no differences in ERα expression. Expression of ERβ decreased estradiol (E2) induced proliferation ability and rate of cells in S-phase cycle. PPT (ERα-specific agonist) and DPN (ERβ-specific agonist) did not show any difference in response, and IC 50 for 4 OH-tamoxifen and fulvestrant did not differ among MCF-7, β-clone 1 and clone 2 (0.05–0.1 μM). Whereas, cell death due to deprivation of E2 from 1nM to 1pM was more frequently observed in ERβ-expressing clones than in parent MCF-7 cell. These cell deaths did not involve standard apoptosis pathway with caspase-3/7 activation and PARP cleavage. E2, DPN and PPT did not affect the proliferation of ERβ-positive triple negative MDA-MB 231 cell, and IC 50 for 4-OH tamoxifen was too high (8 μM) to be achieved in clinical pharmacological dose. Conclusions: From our cell study, better prognosis of ERβ-positive breast cancer patient who treated with adjuvant tamoxifen is mainly due to its own favorable biological behavior. However, this prognostic impact may include the favorable response to the treatment, when we use estrogen-deprivation therapy such as aromatase inhibitors (AIs). Additional clinical study in AI users would be required to address this issue. No significant financial relationships to disclose.

Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, estrogen receptor-positive breast cancer patients: results of a multicentric Italian study. Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group.

1990 ◽  
Vol 8 (8) ◽  
pp. 1310-1320 ◽  
Author(s):  
F Boccardo ◽  
A Rubagotti ◽  
P Bruzzi ◽  
M Cappellini ◽  
G Isola ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Postmenopausal Women ◽  
Cancer Patients ◽  
Combined Treatment ◽  
Tamoxifen Treatment ◽  
Breast Cancer Patients ◽  
Node Positive ◽  
Er Positive ◽  
Positive Breast Cancer

Between November 1, 1983 and June 30, 1987, 510 node-positive, estrogen receptor (ER)-positive breast cancer patients have been randomly allocated to receive either chemotherapy (six intravenous [IV] cyclophosphamide, methotrexate, and fluorouracil [CMF] courses followed by four IV epirubicin courses) or 5 years of tamoxifen treatment or a combination of both therapies. After a median follow-up of 40 months, patients receiving the combined treatment achieved the best results, and those treated with chemotherapy alone achieved the worst, the difference being particularly evident in postmenopausal women. However, while the concurrent use of chemotherapy and tamoxifen did improve the results achieved by chemotherapy alone, particularly in postmenopausal women and in those with four or more involved nodes, it did not significantly improve the results achieved by tamoxifen alone, particularly in patients with higher ER tumor concentrations. Side effects were more numerous and more severe in patients receiving chemotherapy (with or without tamoxifen). Our findings, although still preliminary, confirm that tamoxifen should be the treatment of choice for postmenopausal breast cancer patients with node-positive, ER-positive tumors. In addition, the findings suggest that tamoxifen may represent a safe alternative to chemotherapy (at least to the cytotoxic regimen we used) for younger women, provided they have ER-positive tumors. In patients with ER-positive tumors, the addition of chemotherapy to tamoxifen does not seem to improve significantly the effectiveness of tamoxifen alone.

The CYP2C19 rs4917623 single nucleotide polymorphism to predict tamoxifen efficacy in estrogen receptor-positive breast cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12001-e12001
Author(s):  
Nobuyasu Yoshimoto ◽  
Akihiro Naito ◽  
Nobuko Kawaguchi ◽  
Miwa Kato ◽  
Naoto Kondo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Patients ◽  
Hazard Ratio ◽  
Breast Cancer Patients ◽  
Single Nucleotide ◽  
Free Survival ◽  
Er Positive ◽  
Tamoxifen Efficacy ◽  
Positive Breast Cancer

e12001 Background: Tamoxifen is a selective estrogen receptor modulator that is widely used to treat estrogen receptor (ER)-positive breast cancer. However, not all patients benefit from the incorporation of tamoxifen into an adjuvant therapy. This is also the case when tamoxifen is used in chemoprevention, since only half of participants benefit from the drug. In order to improve treatment response, we attempted to identify single nucleotide polymorphisms (SNPs) that correlated with tamoxifen efficacy. Methods: ER-positive breast cancer patients at our hospital were enrolled on this study between January 2007 and September 2010. The primary endpoint was ER-positive breast cancer-free survival. We examined 17 SNPs in these patients. The survival benefit associated with each genotype was determined with a log-rank test, and the hazard ratio was analyzed using a Cox proportional-hazards model. Results: The median follow-up time of the 320 patients enrolled on the study was 3298 days. Of 240 patients who received any endocrine therapy, ER-positive breast cancer-free survival in patients with the 2q35 rs13387042 AA genotype was significantly shorter than in those who had the AG or GG genotype (p < 0.0001), and the hazard ratio was significantly higher (HR 8.83; 95% CI 2.09–25.53, p = 0.0064). Of the 145 patients who received tamoxifen therapy, there was a trend among ER-positive breast cancer patients with the CYP2C19 rs4917623 TT genotype to have a shorter disease-free period (p = 0.0635) when compared to patients with TC or CC genotypes. Similarly, there was a trend for the TT genotype patients to exhibit a higher hazard ratio (HR 2.62; 95% CI 0.86–7.55, p = 0.0861). Conclusions: The rs4917623 SNP in the CYP2C19 gene, which encodes a metabolic enzyme, predicts tamoxifen efficacy. This finding will facilitate selection of ER-positive breast cancer patients for tamoxifen treatment; it may also be useful for selection of patients most likely to benefit from tamoxifen-dependent chemoprevention.

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