scholarly journals Quercetin Inhibits Lef1 and Resensitizes Docetaxel-Resistant Breast Cancer Cells

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2576 ◽  
Author(s):  
Marta Prieto-Vila ◽  
Iwao Shimomura ◽  
Akiko Kogure ◽  
Wataru Usuba ◽  
Ryou-u Takahashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Metastatic Breast ◽  
Drug Resistant ◽  
Breast Cancer Patients ◽  
Phase I Clinical Trials ◽  
Pathway Activation ◽  
Promising Therapeutic Approach ◽  
Cav1 Expression ◽  
Resistant Cells

Drug resistance is a major problem for breast cancer patients. Docetaxel is an anti-mitotic agent that serves as first line of treatment in metastatic breast cancer, however it is susceptible to cellular drug resistance. Drug-resistant cells are able to spread during treatment, leading to treatment failure and eventually metastasis, which remains the main cause for cancer-associated death. In previous studies, we used single-cell technologies and identified a set of genes that exhibit increased expression in drug-resistant cells, and they are mainly regulated by Lef1. Furthermore, upregulating Lef1 in parental cells caused them to become drug resistant. Therefore, we hypothesized that inhibiting Lef1 could resensitize cells to docetaxel. Here, we confirmed that Lef1 inhibition, especially on treatment with the small molecule quercetin, decreased the expression of Lef1 and resensitized cells to docetaxel. Our results demonstrate that Lef1 inhibition also downregulated ABCG2, Vim, and Cav1 expression and equally decreased Smad-dependent TGF-β signaling pathway activation. Likewise, these two molecules worked in a synergetic manner, greatly reducing the viability of drug-resistant cells. Prior studies in phase I clinical trials have already shown that quercetin can be safely administered to patients. Therefore, the use of quercetin as an adjuvant treatment in addition to docetaxel for the treatment of breast cancer may be a promising therapeutic approach.

scholarly journals The PI3K Pathway: Background and Treatment Approaches

Breast Care ◽  
2016 ◽  
Vol 11 (6) ◽  
pp. 398-404 ◽  
Author(s):  
Michael P. Lux ◽  
Peter A. Fasching ◽  
Michael G. Schrauder ◽  
Alexander Hein ◽  
Sebastian M. Jud ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Tamoxifen Treatment ◽  
Breast Cancer Patients ◽  
Secondary Resistance ◽  
Treatment Approaches ◽  
Metastatic Breast Carcinoma ◽  
Promising Therapeutic Approach

Two-thirds of all breast cancer patients with metastases have a hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative subtype. Endocrine therapy is the treatment of choice in these patients since in addition to its effectiveness it can also maintain the patients' quality of life over a longer term. However, 44-62% of postmenopausal patients with metastatic breast carcinoma have primary tamoxifen resistance. After 3-5 years, 30-40% of the patients receiving tamoxifen treatment develop secondary resistance. Understanding the way in which resistance develops is therefore essential for developing treatment approaches that can prevent or reverse endocrine resistance. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a central role here. As a result of the numerous interactions involved, complex issues arise that need to be taken into account in the development and use of therapeutic agents. In addition, this signaling pathway is the one that most frequently undergoes mutations in breast cancer. The prognostic and predictive significance of individual mutations has not yet been fully explained, but it might provide a basis for patient selection in clinical studies. Initial research results on the use of PI3K inhibitors suggest that this may be a highly promising therapeutic approach, with an acceptable side effect profile.

Biopsy-driven study to identify biomarkers of drug resistance in patients with triple-negative breast cancer.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 87-87
Author(s):  
Adriana Aguilar-Mahecha ◽  
Josiane Lafleur ◽  
Elaheh Ahmadzadeh ◽  
Ewa Przybytkowski ◽  
Carole Seguin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cell Lines ◽  
Triple Negative ◽  
Acquired Resistance ◽  
Great Difficulty ◽  
Clinical Samples ◽  
Drug Resistant ◽  
Breast Cancers ◽  
Breast Cancer Patients

87 Background: Resistance to chemotherapy is the underlying cause of death in most patients dying of breast cancer. Patients with early stages of breast cancer whose tumor is or becomes resistant to chemotherapy have a poor prognosis, while women with advanced breast cancer live as long as their tumors respond to chemotherapy. Because of the great difficulty of obtaining clinical samples from drug resistant tumors in patients, there is scant information about molecular factors from actual drug resistant tumors. This project aims to systematically profile resistant triple negative breast cancers (TNBCs) in order to discover molecular “resistance” genes/proteins as a first step to develop strategies to overcome drug resistance. Methods: Paired biopsies are collected from TNBC patients (NCT01276899). Four needle core biopsies are collected before the initiation of treatment and 2 weeks before surgery or at the time of progression in the neoadjuvant and metastatic settings respectively. Paired biopsies will undergo Next Gen Sequencing, flow sorted aCGH analysis, gene expression and miRNA profiling as well as phosphoproteomic profiling using reverse phase protein arrays. Results: We have currently enrolled 28 patients in the neoadjuvant setting and 3 metastatic patients. We have standardized the methods of collection and processing of tissue and blood specimens to ensure their molecular integrity and compatibility with different genomic and proteomic molecular platforms. Analysis of tumor cellularity has been incorporated into our quality control and we have optimized the extraction of nucleic acids to obtain high yields and optimal quality. In parallel, we have generated acquired resistance to paclitaxel in a panel of TNBC cell lines. These cell lines will also undergo genomic profiling and exome sequencing to identify molecular markers of resistance that will be correlated with the markers found in patient samples. Conclusions: This project will allow us to identify the molecular factors responsible for drug resistance in TNBCs and enable the elaboration of strategies to overcome resistance.

scholarly journals Drug-resistant cancer cell-derived exosomal EphA2 promotes breast cancer metastasis via the EphA2-Ephrin A1 reverse signaling

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Zicong Gao ◽  
Xingxing Han ◽  
Yuying Zhu ◽  
He Zhang ◽  
Ran Tian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Resistant Cell ◽  
Breast Cancer Progression ◽  
Drug Resistant ◽  
Drug Resistant Cell ◽  
Resistant Cells

AbstractTumor metastasis induced by drug resistance is a major challenge in successful cancer treatment. Nevertheless, the mechanisms underlying the pro-invasive and metastatic ability of drug resistance remain elusive. Exosome-mediated intercellular communications between cancer cells and stromal cells in tumor microenvironment are required for cancer initiation and progression. Recent reports have shown that communications between cancer cells also promote tumor aggression. However, little attention has been regarded on this aspect. Herein, we demonstrated that drug-resistant cell-derived exosomes promoted the invasion of sensitive breast cancer cells. Quantitative proteomic analysis showed that EphA2 was rich in exosomes from drug-resistant cells. Exosomal EphA2 conferred the invasive/metastatic phenotype transfer from drug-resistant cells to sensitive cells. Moreover, exosomal EphA2 activated ERK1/2 signaling through the ligand Ephrin A1-dependent reverse pathway rather than the forward pathway, thereby promoting breast cancer progression. Our findings indicate the key functional role of exosomal EphA2 in the transmission of aggressive phenotype between cancer cells that do not rely on direct cell–cell contact. Our study also suggests that the increase of EphA2 in drug-resistant cell-derived exosomes may be an important mechanism of chemotherapy/drug resistance-induced breast cancer progression.

scholarly journals Peritoneal Metastasis After Treated With Abemaciclib Plus Fulvestrant for Metastatic Invasive Lobular Breast Cancer: A Case Report and Review of the Literature

2021 ◽  
Vol 12 ◽  
Author(s):  
Hong-Fei Gao ◽  
Jun-Sheng Zhang ◽  
Qiang-Zu Zhang ◽  
Teng Zhu ◽  
Ci-Qiu Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Peritoneal Metastasis ◽  
Lobular Carcinoma ◽  
Palliative Therapy ◽  
Metastatic Breast ◽  
Peritoneal Metastases ◽  
Breast Cancer Patients ◽  
Adequate Treatment ◽  
Metastatic Lesions

Peritoneal metastases from invasive lobular carcinoma (ILC) of breast are uncommon and usually related to poor prognosis due to difficulty of detection in clinical practice and drug resistance. Therefore, recognizing the entities of peritoneal metastases of ILC and the potential mechanism of drug resistance is of great significance for early detection and providing accurate management. We herein report a case of a 60-year-old female who presented with nausea and vomiting as the first manifestation after treated with abemaciclib (a CDK4/6 inhibitor) plus fulvestrant for 23 months due to bone metastasis of ILC. Exploratory laparotomy found multiple nodules in the peritoneum and omentum, and immunohistochemistry confirmed that the peritoneal metastatic lesions were consistent with ILC. Palliative therapy was initiated, but the patient died two months later due to disease progression with malignant ascites. Whole exome sequencing (WES) was used to detect the tumor samples and showed the peritoneal metastatic lesions had acquired ESR1 and PI3KCA mutations, potentially explaining the mechanism of endocrine therapy resistance. We argue that early diagnosis of peritoneal metastasis from breast cancer is crucial for prompt and adequate treatment and WES might be an effective supplementary technique for detection of potential gene mutations and providing accurate treatment for metastatic breast cancer patients.

scholarly journals Drug-resistant cancer cell-derived exosomal EphA2 promotes breast cancer metastasis via the EphA2-Ephrin A1 reverse signaling

2020 ◽  
Author(s):  
Zicong Gao ◽  
Xingxing Han ◽  
Yuying Zhu ◽  
He Zhang ◽  
Ran Tian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Resistant Cell ◽  
Migration And Invasion ◽  
Drug Resistant ◽  
Resistant Cells

Abstract Background: The failure of chemotherapy is accompanied by the emergence of drug resistance and tumor relapse. Tumor metastasis induced by drug resistance is a major challenge in successful cancer treatment. Nevertheless, the mechanisms underlying the pro-invasive and metastatic ability of drug resistance remain elusive. Exosome-mediated intercellular communications between cancer cells and stromal cells in tumor microenvironment are required for cancer initiation and progression. Recent reports have shown that communications between cancer cells also promote tumor aggression. However, little attention has been regarded on this aspect. In this study, we aimed to investigate the mechanisms of exosomes derived from drug-resistant cells in regulating the invasion and metastasis of sensitive breast cancer cells.Methods: Exosomes isolated from drug-resistant breast cancer cells and their parental cells were used to treat breast cancer cells, and then the migration and invasion abilities were examined. The tandem mass tag (TMT)-based quantitative proteomic method was carried out to identify key molecules that regulate cancer aggressiveness. Lentivirus-mediated shRNAs, overexpression, point mutation, truncation mutation, Western blotting, tumor xenograft mice models, and in vivo breast cancer metastatic models were used to investigate the functional role of EphA2 on the invasion and metastatic potential of breast cancer cells.Results: We demonstrated that drug-resistant cell-derived exosomes promoted the migration and invasion of sensitive breast cancer cells. Quantitative proteomic analysis showed that EphA2 was rich in exosomes from drug-resistant cells. Exosomal EphA2 conferred the invasive/metastatic phenotype transfer from drug-resistant cells to sensitive cells. In addition, we provided considerable evidence that exosomal EphA2 activated ERK1/2 signaling through the ligand Ephrin A1-dependent reverse pathway rather than the forward pathway, thereby promoting breast cancer progression. Conclusions: Our findings indicate the key functional role of exosomal EphA2 in the transmission of aggressive phenotype between cancer cells that do not rely on direct cell–cell contact. Our study also suggests that the increase of EphA2 in drug-resistant cell-derived exosomes may be an important mechanism of chemotherapy/drug resistance-induced breast cancer progression.

scholarly journals Fine analysis of atypical circulating tumor cells in metastatic breast cancer patients reveals subsets with different prognostic values

2020 ◽  
Author(s):  
Alexia Lopresti ◽  
Laurys Boudin ◽  
Pascal Finetti ◽  
Séverine Garnier ◽  
Anaïs Aulas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Circulating Cells

Purpose: Circulating tumor cells (CTCs) have a tremendous potential for diagnosis and treatment of breast cancer patients. Here, we performed a unique analysis of all atypical circulating cells isolated with a filtration-based technology from metastatic breast cancer (mBC) patients. Patients and methods: The PERMED-01 study enrolled patients with mBC, refractory to systemic therapy, and with an accessible lesion to biopsy. We analyzed atypical circulating cells isolated from patients' blood at the time of inclusion using Screencell® Cyto device. For 23 out of 91 analyzed patients, this was completed by advanced immunofluorescence staining of atypical circulating cells. Subsets cut-offs were established using a two-component Gaussian finite Mixture Model, and evaluated for correlation with clinico-pathological data, including progression-free survival (PFS) and overall survival (OS). Results: Three subsets of atypical circulating cells, absent from controls (n=7), were observed in cancer patients (n=91): isolated (iCTCs), Clusters (CTM), and Giant CTCs (gCTCs). CTCs' median number was 8.33 per mL. Co-expression of stem and drug resistance markers was associated with intermediate epithelial to mesenchymal transition phenotype in CTM and gCTCs, but not in iCTCs. Presence of gCTC was associated with shorter PFS and OS. Concerning PFS, assigning an immunofluorescence-based Epithelial to Mesenchymal status improved their prognostic value. Conclusion: This study brings to light the diversity of CTCs in mBC patients and their specific molecular profiles regarding epithelial to mesenchymal transition, stemness and drug resistance status. It also highlights the involvement of an atypical circulating cell subset, the gCTCs, as a prognostic factor for PFS and OS.

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