Transcriptional profiling of patient-matched ER-positive breast cancer tissue from post-menopausal women treated with neoadjuvant RAD001.

2009 ◽  
Author(s):  
VS Sabine ◽  
AH Sims ◽  
EJ Macaskill ◽  
L Renshaw ◽  
JS Thomas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcriptional Profiling ◽  
Breast Cancer Tissue ◽  
Cancer Tissue ◽  
Menopausal Women ◽  
Er Positive ◽  
Post Menopausal ◽  
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.

Is incomplete estradiol suppression during aromatase inhibitor treatment in post-menopausal patients with breast cancer due to insufficient systemic drug concentrations?

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1063-1063
Author(s):  
Daniel Louis Hertz ◽  
Kelley M. Kidwell ◽  
Kelly A Speth ◽  
Christina L Gersch ◽  
Zeruesenay Desta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Logistic Regression ◽  
Plasma Concentrations ◽  
High Plasma ◽  
Limit Of Quantification ◽  
Drug Concentrations ◽  
Menopausal Women ◽  
Er Positive ◽  
Post Menopausal ◽  
Positive Breast Cancer

1063 Background: Aromatase inhibitors (AI) suppress estrogen biosynthesis and are effective treatments for estrogen receptor (ER)-positive breast cancer. In a prospectively enrolled cohort we observed a subset of post-menopausal women who exhibit high plasma estradiol (E2) concentrations during AI treatment, which could potentially contribute to treatment failure. We tested the hypothesis that incomplete E2 suppression is due to insufficient systemic AI concentrations. Methods: Five hundred post-menopausal women with ER-positive breast cancer were randomized to daily exemestane (Exe) 25 mg or letrozole (Let) 2.5 mg. Plasma E2 was measured using GC/MS/MS (lower limit of quantification (LLOQ) = 1.25 pg/mL) at baseline and after 3 months. Let and Exe plasma concentrations measured after 1 or 3 months were compared with the magnitude of E2 depletion using four complementary statistical procedures to assess associations of drug concentrations with: 1) a binary outcome of E2 suppression below LLOQ (logistic regression), 2) 3-month E2 concentrations (linear regression), 3) absolute change from baseline in E2 concentrations (Spearman correlation), and 4) an ordinal outcome defined by E2: decreased to below LLOQ, decreased but not to LLOQ, stayed the same, or increased from baseline (cumulative logistic regression). Results: 397 patients with E2 and AI concentration measurements were evaluable (Exe n = 199, Let n = 198). Thirty (7.6%) patients (Exe n = 13, Let n = 17) had E2 concentrations above the LLOQ at 3 months (range: 1.42-63.8 pg/mL). Exe and Let concentrations were not associated with achievement of unmeasurable E2 concentrations, on-treatment E2 concentrations, E2 change from baseline, or ordinal groupings of E2 change (all p > 0.05). In a parallel analysis there was no association of estrone-sulfate and drug concentrations (data not shown). Conclusions: Our results suggest that circulating drug concentrations do not explain incomplete E2 suppression in women receiving AI therapy. Additional studies are underway to determine whether age, body mass and genetic variation in the aromatase enzyme influence AI treatment response.

scholarly journals miR-1290 and its potential targets are associated with characteristics of estrogen receptor α-positive breast cancer

2012 ◽  
Vol 20 (1) ◽  
pp. 91-102 ◽  
Author(s):  
Yumi Endo ◽  
Tatsuya Toyama ◽  
Satoru Takahashi ◽  
Nobuyasu Yoshimoto ◽  
Mai Iwasa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Target Genes ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Estrogen Receptor Α ◽  
Breast Cancer Tissue ◽  
Cancer Tissue ◽  
Er Positive ◽  
Positive Breast Cancer

Recent analyses have identified heterogeneity in estrogen receptor α (ERα)-positive breast cancer. Subtypes called luminal A and luminal B have been identified, and the tumor characteristics, such as response to endocrine therapy and prognosis, are different in these subtypes. However, little is known about how the biological characteristics of ER-positive breast cancer are determined. In this study, expression profiles of microRNAs (miRNAs) and mRNAs in ER-positive breast cancer tissue were compared between ERhighKi67lowtumors and ERlowKi67hightumors by miRNA and mRNA microarrays. Unsupervised hierarchical clustering analyses revealed distinct expression patterns of miRNAs and mRNAs in these groups. We identified a downregulation of miR-1290 in ERhighKi67lowtumors. Among 11 miRNAs that were upregulated in ERhighKi67lowtumors, quantitative RT-PCR detection analysis using 64 samples of frozen breast cancer tissue identified six miRNAs (let-7a, miR-15a, miR-26a, miR-34a, miR-193b, and miR-342-3p). We picked up 11 genes that were potential target genes of the selected miRNAs and that were differentially expressed in ERhighKi67lowtumors and ERlowKi67hightumors. Protein expression patterns of the selected target genes were analyzed in 256 ER-positive breast cancer samples by immunohistochemistry: miR-1290 and its putative targets,BCL2, FOXA1, MAPT, andNAT1, were identified. Transfection experiments revealed that introduction of miR-1290 into ER-positive breast cancer cells decreased expression of NAT1 and FOXA1. Our results suggest that miR-1290 and its potential targets might be associated with characteristics of ER-positive breast cancer.

Decreased background parenchymal enhancement of the contralateral breast after two cycles of neoadjuvant chemotherapy is associated with tumor response in HER2-positive breast cancer

2017 ◽  
Vol 59 (7) ◽  
pp. 806-812 ◽  
Author(s):  
Chao You ◽  
Yajia Gu ◽  
Wen Peng ◽  
Jianwei Li ◽  
Xuxia Shen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Response ◽  
Early Stage ◽  
Contralateral Breast ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Background Parenchymal Enhancement ◽  
Menopausal Women ◽  
Post Menopausal ◽  
Positive Breast Cancer

Background Several recent studies have focused on the association between background parenchymal enhancement (BPE) and tumor response to neoadjuvant chemotherapy (NAC), but early prediction of tumor response based on BPE has yet not been investigated. Purpose To retrospectively investigate whether changes in the BPE of the contralateral breast following NAC could help predict tumor response in early stage HER2-positive breast cancer. Material and Methods Data from 71 patients who were diagnosed with unilateral HER2 positive breast cancer and then underwent NAC with trastuzumab before surgery were analyzed retrospectively. Two experienced radiologists independently categorized the patients’ levels of BPE of the contralateral breast into four categories (1 = minimal, 2 = mild, 3 = moderate, 4 = marked) at baseline and after the second cycle of NAC. After undergoing surgery, 34 patients achieved pathologic complete response (pCR) and 37 patients had residual disease (non-pCR). The association between BPE and histopathologic tumor response was analyzed. Result The level of BPE was higher in premenopausal than post-menopausal women both at baseline and after the second cycle of NAC ( P < 0.005). A significant reduction in BPE ( P < 0.001) was observed after the second NAC cycle; however, a more obvious decrease in BPE was identified in premenopausal relative to post-menopausal women ( P = 0.041). No significant association was identified between pCR and baseline BPE ( P = 0.287). However, after the second NAC cycle, decreased BPE was significantly associated with pCR ( P = 0.003). Conclusion For HER2-positive patients, changes in BPE may serve as an additional imaging biomarker of treatment response at an early stage.

scholarly journals A novel culture method that sustains ERα signaling in human breast cancer tissue microstructures

2020 ◽  
Author(s):  
Ana Luísa Cartaxo ◽  
Marta F Estrada ◽  
Giacomo Domenici ◽  
Ruben Roque ◽  
Fernanda Silva ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Human Breast Cancer ◽  
Ex Vivo ◽  
Breast Cancer Tissue ◽  
Cancer Tissue ◽  
Breast Cancers ◽  
Human Breast ◽  
Human Breast Cancer Tissue ◽  
Positive Breast Cancer

Abstract Background Estrogen receptor α (ERα) signaling is a defining and driving event in most breast cancers; ERα is detected in malignant epithelial cells of 75% of all breast cancers (classified as ER-positive breast cancer) and, in these cases, ERα targeting is the main therapeutic strategy. However, the biological determinants of ERα heterogeneity and the mechanisms underlying therapeutic resistance are still elusive, hampered by the challenges in developing experimental models recapitulative of intra-tumoral heterogeneity and in which ERα signaling is sustained. Ex vivo cultures of human breast cancer tissue have been proposed to retain the original tissue architecture, epithelial and stromal cell components and ERα. However, loss of cellularity, viability and ERα expression are well-known culture-related phenomena. Methods BC samples were collected and brought to the laboratory. Then they were minced, enzymatically digested, entrapped in alginate and cultured for one month. The histological architecture, cellular composition and cell proliferation of tissue microstructures were assessed by immunohistochemistry. Cell viability was assessed by measurement of cell metabolic activity. The presence of ERα was accessed by immunohistochemistry and RT-qPCR and its functionality evaluated by challenge with 17−β−estradiol and fulvestrant, respectively. Results We describe a strategy based on entrapment of breast cancer tissue microstructures in alginate capsules and their long-term culture under agitation, successfully applied to tissue obtained from 63 breast cancer patients. After one month in culture, the architectural features of the encapsulated tissue microstructures were similar to the original patient tumors: epithelial, stromal and endothelial compartments were maintained with an average of 97 of cell viability compared to day 0. In ERα-positive cases, fibers of collagen, the main extracellular matrix component in vivo , were preserved. ERα expression was retained at gene and protein levels and response to ERα stimulation and inhibition was observed at the level of downstream targets, demonstrating active ER signaling. Conclusions The proposed model system is a new methodology to study ex vivo breast cancer biology, in particular ERα signaling. It is suitable for interrogating the long-term effects of anti-endocrine drugs in a set-up that closely resembles the original tumor microenvironment, with potential application in pre- and co-clinical assays of ERα-positive breast cancer.

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