Targeting PSG1 to enhance chemotherapeutic efficacy: new application for anti-coagulant the dicumarol

2016 ◽  
Vol 130 (24) ◽  
pp. 2267-2276 ◽  
Author(s):  
Dong-xu He ◽  
Feng Gu ◽  
Jian Wu ◽  
Xiao-Ting Gu ◽  
Chun-Xiao Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Transforming Growth Factor ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Transforming Growth Factor Β ◽  
Clinical Samples ◽  
Breast Cancer Patients

Chemotherapeutic response is critical for the successful treatment and good prognosis in cancer patients. In this study, we analysed the gene expression profiles of preoperative samples from oestrogen receptor (ER)-negative breast cancer patients with different responses to taxane-anthracycline-based (TA-based) chemotherapy, and identified a group of genes that was predictive. Pregnancy specific beta-1-glycoprotein 1 (PSG1) played a central role within signalling pathways of these genes. Inhibiting PSG1 can effectively reduce chemoresistance via a transforming growth factor-β (TGF-β)-related pathway in ER-negative breast cancer cells. Drug screening then identified dicumarol (DCM) to target the PSG1 and inhibit chemoresistance to TA-based chemotherapy in vitro, in vivo, and in clinical samples. Taken together, this study highlights PSG1 as an important mediator of chemoresistance, whose effect could be diminished by DCM.

Targeting PKM2 promotes chemosensitivity of breast cancer cells in vitro and in vivo

2021 ◽  
pp. 1-10
Author(s):  
Yu Wang ◽  
Han Zhao ◽  
Ping Zhao ◽  
Xingang Wang
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Poor Prognosis ◽  
Breast Cancer Cells ◽  
Breast Cancer Patients ◽  
Cancer Tissues

BACKGROUND: Pyruvate kinase M2 (PKM2) was overexpressed in many cancers, and high PKM2 expression was related with poor prognosis and chemoresistance. OBJECTIVE: We investigated the expression of PKM2 in breast cancer and analyzed the relation of PKM2 expression with chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated whether PKM2 could reverse chemoresistance in breast cancer cells in vitro and in vivo. METHODS: Immunohistochemistry (IHC) was performed in 130 surgical resected breast cancer tissues. 78 core needle biopsies were collected from breast cancer patients before neoadjuvant chemotherapy. The relation of PKM2 expression and multi-drug resistance to NAC was compared. The effect of PKM2 silencing or overexpression on Doxorubicin (DOX) sensitivity in the MCF-7 cells in vitro and in vivo was compared. RESULTS: PKM2 was intensively expressed in breast cancer tissues compared to adjacent normal tissues. In addition, high expression of PKM2 was associated with poor prognosis in breast cancer patients. The NAC patients with high PKM2 expression had short survival. PKM2 was an independent prognostic predictor for surgical resected breast cancer and NAC patients. High PKM2 expression was correlated with neoadjuvant treatment resistance. High PKM2 expression significantly distinguished chemoresistant patients from chemosensitive patients. In vitro and in vivo knockdown of PKM2 expression decreases the resistance to DOX in breast cancer cells in vitro and tumors in vivo. CONCLUSION: PKM2 expression was associated with chemoresistance of breast cancers, and could be used to predict the chemosensitivity. Furthermore, targeting PKM2 could reverse chemoresistance, which provides an effective treatment methods for patients with breast cancer.

scholarly journals Integrin alpha5 in human breast cancer is a mediator of bone metastasis and a therapeutic target for the treatment of osteolytic lesions

Oncogene ◽  
2021 ◽  
Author(s):  
Francesco Pantano ◽  
Martine Croset ◽  
Keltouma Driouch ◽  
Natalia Bednarz-Knoll ◽  
Michele Iuliani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Bone Metastasis ◽  
Tumor Cell ◽  
Cancer Patients ◽  
Breast Cancer Patients ◽  
Osteolytic Lesions ◽  
Cell Colonization

AbstractBone metastasis remains a major cause of mortality and morbidity in breast cancer. Therefore, there is an urgent need to better select high-risk patients in order to adapt patient’s treatment and prevent bone recurrence. Here, we found that integrin alpha5 (ITGA5) was highly expressed in bone metastases, compared to lung, liver, or brain metastases. High ITGA5 expression in primary tumors correlated with the presence of disseminated tumor cells in bone marrow aspirates from early stage breast cancer patients (n = 268; p = 0.039). ITGA5 was also predictive of poor bone metastasis-free survival in two separate clinical data sets (n = 855, HR = 1.36, p = 0.018 and n = 427, HR = 1.62, p = 0.024). This prognostic value remained significant in multivariate analysis (p = 0.028). Experimentally, ITGA5 silencing impaired tumor cell adhesion to fibronectin, migration, and survival. ITGA5 silencing also reduced tumor cell colonization of the bone marrow and formation of osteolytic lesions in vivo. Conversely, ITGA5 overexpression promoted bone metastasis. Pharmacological inhibition of ITGA5 with humanized monoclonal antibody M200 (volociximab) recapitulated inhibitory effects of ITGA5 silencing on tumor cell functions in vitro and tumor cell colonization of the bone marrow in vivo. M200 also markedly reduced tumor outgrowth in experimental models of bone metastasis or tumorigenesis, and blunted cancer-associated bone destruction. ITGA5 was not only expressed by tumor cells but also osteoclasts. In this respect, M200 decreased human osteoclast-mediated bone resorption in vitro. Overall, this study identifies ITGA5 as a mediator of breast-to-bone metastasis and raises the possibility that volociximab/M200 could be repurposed for the treatment of ITGA5-positive breast cancer patients with bone metastases.

scholarly journals Blockade of CDK7 Reverses Endocrine Therapy Resistance in Breast Cancer

2020 ◽  
Vol 21 (8) ◽  
pp. 2974 ◽  
Author(s):  
Yasmin M. Attia ◽  
Samia A. Shouman ◽  
Salama A. Salama ◽  
Cristina Ivan ◽  
Abdelrahman M. Elsayed ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Volume ◽  
Apoptotic Cell ◽  
Therapy Resistance ◽  
Tamoxifen Treatment ◽  
Clinical Samples ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients

Cyclin-dependent kinase (CDK)-7 inhibitors are emerging as promising drugs for the treatment of different types of cancer that show chemotherapy resistance. Evaluation of the effects of CDK7 inhibitor, THZ1, alone and combined with tamoxifen is of paramount importance. Thus, in the current work, we assessed the effects of THZ1 and/or tamoxifen in two estrogen receptor-positive (ER+) breast cancer cell lines (MCF7) and its tamoxifen resistant counterpart (LCC2) in vitro and in xenograft mouse models of breast cancer. Furthermore, we evaluated the expression of CDK7 in clinical samples from breast cancer patients. Cell viability, apoptosis, and genes involved in cell cycle regulation and tamoxifen resistance were determined. Tumor volume and weight, proliferation marker (Ki67), angiogenic marker (CD31), and apoptotic markers were assayed. Bioinformatic data indicated CDK7 expression was associated with negative prognosis, enhanced pro-oncogenic pathways, and decreased response to tamoxifen. Treatment with THZ1 enhanced tamoxifen-induced cytotoxicity, while it inhibited genes involved in tumor progression in MCF-7 and LCC2 cells. In vivo, THZ1 boosted the effect of tamoxifen on tumor weight and tumor volume, reduced Ki67 and CD31 expression, and increased apoptotic cell death. Our findings identify CDK7 as a possible therapeutic target for breast cancer whether it is sensitive or resistant to tamoxifen therapy.

scholarly journals LncRNA HCP5 Encoding Protein Regulates Ferroptosis To Promote The Progression of Triple Negative Breast Cancer

2021 ◽  
Author(s):  
Xiao Tong ◽  
Jiani Xing ◽  
Haizhou Liu ◽  
Shunheng Zhou ◽  
Yue Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Patients ◽  
Encoding Protein ◽  
Coding Capacity

Abstract Background Long non-coding RNAs (lncRNAs) is widely described as a class of RNA longer than 200 nucleotides without encoding capability. But recent years, more and more open reading frames (ORFs) have been found in lncRNAs which indicate they have coding capacity. But the mechanisms of the encoding products in cancer are mostly unknown. We have previously shown lncRNA HCP5 is an oncogene in triple negative breast cancer (TNBC), and the aim of the current study was to investigate if lncRNA HCP5 encoding protein promotes TNBC by regulating ferroptosis. Methods We use bioinformatics to predict coding capacity. Molecular biology experiments and the xenograft assay in nude mice to study the mechanism of lncRNA HCP5 encoding protein. And the protein expression was evaluated in a tissue microarray of 140 invasive breast tumors and 45 pared precancerous breast tissues. Association between the protein expression and clinicopathologic features of breast cancer patients was analyzed. Results In this study, we identify that ORF in lncRNA HCP5 can encode a conserved protein with 132-amino acid. The protein, which is named HCP5-132aa, promotes TNBC growth. Mechanistically, the HCP5-132aa regulates GPX4 expression and lipid ROS level through ferroptosis pathway to promote TNBC progression. HCP5-132aa ORF knockdown synergizes with ferroptosis activators in vitro and in vivo. Breast cancer patients with high levels of HCP5-132aa have poorer prognosis. Conclusions Our study indicates that overexpression of lncRNA HCP5 encoding protein is a critical oncogenic event in TNBC. Our findings uncover a regulatory mechanism of ferroptosis in TNBC orchestrated by a protein encoded by an lncRNA.

scholarly journals Gene expression in mouse ovarian follicle development in vivo versus an ex vivo alginate culture system

Reproduction ◽  
2011 ◽  
Vol 142 (2) ◽  
pp. 309-318 ◽  
Author(s):  
Elizabeth M Parrish ◽  
Anaar Siletz ◽  
Min Xu ◽  
Teresa K Woodruff ◽  
Lonnie D Shea
Keyword(s):  
Gene Expression ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Expression Profiles ◽  
Ovarian Follicle ◽  
Gene Expression Profiles ◽  
Follicle Development ◽  
Α Subunit

Ovarian follicle maturation results from a complex interplay of endocrine, paracrine, and direct cell–cell interactions. This study compared the dynamic expression of key developmental genes during folliculogenesis in vivo and during in vitro culture in a 3D alginate hydrogel system. Candidate gene expression profiles were measured within mouse two-layered secondary follicles, multi-layered secondary follicles, and cumulus–oocyte complexes (COCs). The expression of 20 genes involved in endocrine communication, growth signaling, and oocyte development was investigated by real-time PCR. Gene product levels were compared between i) follicles of similar stage and ii) COCs derived either in vivo or by in vitro culture. For follicles cultured for 4 days, the expression pattern and the expression level of 12 genes were the same in vivo and in vitro. Some endocrine (cytochrome P450, family 19, subfamily A, polypeptide 1 (Cyp19a1) and inhibin βA subunit (Inhba)) and growth-related genes (bone morphogenetic protein 15 (Bmp15), kit ligand (Kitl), and transforming growth factor β receptor 2 (Tgfbr2)) were downregulated relative to in vivo follicles. For COCs obtained from cultured follicles, endocrine-related genes (inhibin α-subunit (Inha) and Inhba) had increased expression relative to in vivo counterparts, whereas growth-related genes (Bmp15, growth differentiation factor 9, and kit oncogene (Kit)) and zona pellucida genes were decreased. However, most of the oocyte-specific genes (e.g. factor in the germline α (Figla), jagged 1 (Jag1), and Nlrp5 (Mater)) were expressed in vitro at the same level and with the same pattern as in vivo-derived follicles. These studies establish the similarities and differences between in vivo and in vitro cultured follicles, guiding the creation of environments that maximize follicle development and oocyte quality.

Genomic Prediction of Locoregional Recurrence After Mastectomy in Breast Cancer

2006 ◽  
Vol 24 (28) ◽  
pp. 4594-4602 ◽  
Author(s):  
Skye H. Cheng ◽  
Cheng-Fang Horng ◽  
Mike West ◽  
Erich Huang ◽  
Jennifer Pittman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Patients ◽  
Expression Profiles ◽  
Eligible Patient ◽  
Gene Expression Profiles ◽  
Breast Cancer Patients ◽  
Predictive Index ◽  
Validation Data ◽  
Data Set

Purpose This study aims to explore gene expression profiles that are associated with locoregional (LR) recurrence in breast cancer after mastectomy. Patients and Methods A total of 94 breast cancer patients who underwent mastectomy between 1990 and 2001 and had DNA microarray study on the primary tumor tissues were chosen for this study. Eligible patient should have no evidence of LR recurrence without postmastectomy radiotherapy (PMRT) after a minimum of 3-year follow-up (n = 67) and any LR recurrence (n = 27). They were randomly split into training and validation sets. Statistical classification tree analysis and proportional hazards models were developed to identify and validate gene expression profiles that relate to LR recurrence. Results Our study demonstrates two sets of gene expression profiles (one with 258 genes and the other 34 genes) to be of predictive value with respect to LR recurrence. The overall accuracy of the prediction tree model in validation sets is estimated 75% to 78%. Of patients in validation data set, the 3-year LR control rate with predictive index more than 0.8 derived from 34-gene prediction models is 91%, and predictive index 0.8 or less is 40% (P = .008). Multivariate analysis of all patients reveals that estrogen receptor and genomic predictive index are independent prognostic factors that affect LR control. Conclusion Using gene expression profiles to develop prediction tree models effectively identifies breast cancer patients who are at higher risk for LR recurrence. This gene expression–based predictive index can be used to select patients for PMRT.

scholarly journals Comparison of gene expression profiles predicting progression in breast cancer patients treated with tamoxifen

2008 ◽  
Vol 113 (2) ◽  
pp. 275-283 ◽  
Author(s):  
Marleen Kok ◽  
Sabine C. Linn ◽  
Ryan K. Van Laar ◽  
Maurice P. H. M. Jansen ◽  
Teun M. van den Berg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Patients ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Breast Cancer Patients
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