scholarly journals H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis

2021 ◽  
Author(s):  
Ayushi Verma ◽  
Akhilesh Singh ◽  
Mushtaq Ahmad Nengroo ◽  
Krishan Kumar Saini ◽  
Abhipsa Sinha ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Peritoneal Metastasis ◽  
Poor Prognosis ◽  
Conclusive Evidence ◽  
Splenic Metastasis ◽  
Live Animal ◽  
Genetic Ablation ◽  
The Impact

AbstractTriple Negative Breast Cancer (TNBC) is known to have poor prognosis and adverse clinical outcome among all breast cancer subtypes due to the absence of available targeted therapy for it. Emerging literature indicates that epigenetic reprogramming is now appreciated as a driving force for TNBC pathophysiology. High expression of epigenetic modulator EZH2 (Enhancer of zeste homolog 2) has been shown to correlate with TNBC poor prognosis but the contribution of EZH2 catalytic (H3K27me3) versus non-catalytic EZH2 (NC-EZH2) function in TNBC growth and progression remains elusive. In the process of dissecting the impact of H3K27me3 versus NC-EZH2 function in TNBC pathogenesis, we reveal that selective hyperactivation of H3K27me3 over NC-EZH2 not only promotes TNBC metastasis but also alters the metastatic landscape of TNBC. Using extensive in- vivo live animal imaging, we present conclusive evidence that peritoneal metastasis, particularly splenic metastasis of TNBC is governed by H3K27me3. Transcriptome analyses of hyperactive H3K27me3 cells lead us to discover Cytokeratin-14 (KRT14) as a new target of H3K27me3. Unlike classical H3K27me3 mediated suppression of gene expression, here; we observe that H3K27me3 enhances KRT14 transcription by attenuating the binding of transcriptional repressor Sp1 to its promoter. Further, loss of KRT14 significantly reduces TNBC migration, invasion and splenic metastasis. Finally, genetic ablation of EZH2 or pharmacological inhibition of EZH2 catalytic function by FDA approved drug tazemetostat (EPZ6438) robustly inhibits TNBC peritoneal metastasis. Altogether, our preclinical findings posit a rational insight for the clinical development of H3K27me3 inhibitor like tazemetostat as a targeted therapy against TNBC.

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.

Breast cancer-related lymphedema and quality of life: A qualitative analysis over years of survivorship

2019 ◽  
pp. 174239531987279
Author(s):  
Allison B Anbari ◽  
Ausanee Wanchai ◽  
Jane M Armer
Keyword(s):  
Breast Cancer ◽  
Quality Of Life ◽  
Healthcare Providers ◽  
Breast Cancer Diagnosis ◽  
Data Saturation ◽  
Breast Cancer Related Lymphedema ◽  
Reported Data ◽  
The Impact

Objectives The study purpose was to examine perspectives of women with newly diagnosed breast cancer-related lymphedema (BCRL) regarding their quality of life over seven years. Method Data were collected over seven years using the Lymphedema and Breast Cancer Questionnaire (LBCQ). Participants with BCRL answered open-ended questions corresponding to changes in mood and lifestyle from post-op through annual interviews and surveys. Self-reported data from 97 participants with BCRL were analyzed using in vivo coding and template-style content analysis to elicit the impact of BCRL on quality of life domains. Results Data saturation was achieved as participants neared 30 to 36 months post- breast cancer diagnosis. Three major themes were identified related to BCRL’s impact on: physical function; daily living and social function; and psychological function. Discussion Findings suggest that BCRL impacts quality of life not only soon after diagnosis, but also throughout survivorship years. Healthcare providers should develop programs to enhance quality of life for survivors with BCRL.

scholarly journals Knockdown of Leptin Receptor Affects Macrophage Phenotype in the Tumor Microenvironment Inhibiting Breast Cancer Growth and Progression

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2078
Author(s):  
Luca Gelsomino ◽  
Giuseppina Daniela Naimo ◽  
Rocco Malivindi ◽  
Giuseppina Augimeri ◽  
Salvatore Panza ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Leptin Receptor ◽  
Macrophage Phenotype ◽  
In Vivo Models ◽  
Monocyte Chemoattractant Protein 1 ◽  
Arginase 1 ◽  
The Impact

Aberrant leptin (Ob) signaling, a hallmark of obesity, has been recognized to influence breast cancer (BC) biology within the tumor microenvironment (TME). Here, we evaluated the impact of leptin receptor (ObR) knockdown in affecting BC phenotype and in mediating the interaction between tumor cells and macrophages, the most abundant immune cells within the TME. The stable knockdown of ObR (ObR sh) in ERα-positive and ERα-negative BC cells turned the tumor phenotype into a less aggressive one, as evidenced by in vitro and in vivo models. In xenograft tumors and in co-culture experiments between circulating monocytes and BC cells, the absence of ObR reduced the recruitment of macrophages, and also affected their cytokine mRNA expression profile. This was associated with a decreased expression and secretion of monocyte chemoattractant protein-1 in ObR sh clones. The loss of Ob/ObR signaling modulated the immunosuppressive TME, as shown by a reduced expression of programmed death ligand 1/programmed cell death protein 1/arginase 1. In addition, we observed increased phagocytic activity of macrophages compared to control Sh clones in the presence of ObR sh-derived conditioned medium. Our findings, addressing an innovative role of ObR in modulating immune TME, may open new avenues to improve BC patient health care.

The Impact of Primary Tumor Surgery on Survival in HER2 Positive Stage IV Breast Cancer Patients in the Current Era of Targeted Therapy

2020 ◽  
Vol 27 (8) ◽  
pp. 2711-2720 ◽  
Author(s):  
Ross Mudgway ◽  
Carlos Chavez de Paz Villanueva ◽  
Ann C. Lin ◽  
Maheswari Senthil ◽  
Carlos A. Garberoglio ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Cancer Patients ◽  
Primary Tumor ◽  
Stage Iv ◽  
Tumor Surgery ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Stage Iv Breast Cancer ◽  
The Impact

scholarly journals Breast Cancer Prevention-Is there a Future for Sulforaphane and Its Analogs?

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1559
Author(s):  
Dominika Kuran ◽  
Anna Pogorzelska ◽  
Katarzyna Wiktorska
Keyword(s):  
Breast Cancer ◽  
Cancer Prevention ◽  
Initial Study ◽  
Dietary Factors ◽  
Breast Cancer Prevention ◽  
In Vivo Studies ◽  
Cancer Etiology ◽  
The Impact

Breast cancer is the most prevalent type of cancer among women worldwide. There are several recommended methods of breast cancer prevention, including chemoprevention. There are several approved drugs used to prevent breast cancer occurrence or recurrence and metastasizing. There are also a number of new substances undergoing clinical trials and at the stage of initial study. Studies suggest that dietary factors play a crucial role in breast cancer etiology. Epidemiological studies indicate that in particular vegetables from the Brassicaceae family are a rich source of chemopreventive substances, with sulforaphane (SFN) being one of the most widely studied and characterized. This review discusses potential applicability of SFN in breast cancer chemoprevention. A comprehensive review of the literature on the impact of SFN on molecular signalling pathways in breast cancer and breast untransformed cells is presented. The presented results of in vitro and in vivo studies show that this molecule has a potential to act as a preventive molecule either to prevent disease development or recurrence and metastasizing, and as a compound protecting normal cells against the toxic effects of cytostatics. Finally, the still scanty attempts to develop an improved analog are also presented and discussed.

scholarly journals Development of Targeted Therapy Therapeutics to Sensitize Triple-Negative Breast Cancer Chemosensitivity Utilizing Bacteriophage phi29 Derived Packaging RNA

2020 ◽  
Author(s):  
Long Zhang ◽  
Chaofeng Mu ◽  
Tinghong Zhang ◽  
Dejun Yang ◽  
Luhui Fan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Sirna Delivery ◽  
Growth Factor Receptor ◽  
Her2 Breast Cancer ◽  
Packaging Rna

Abstract Background: To date, triple-negative breast cancer (TNBC) treatment options are limited due to it lacks expression of receptors and are only available managed with chemotherapy. What's worse, TNBC is frequently developing resistance to chemotherapy. By using siRNA-based therapeutics, our recent work demonstrated X-box-binding protein 1 (XBP1) was linked to HER2+ breast cancer development and chemoresistance. As is well-known, the instability, off-target effects, net negative charge, and hydrophobicity of siRNA hamper its’ in vivo utilization and clinical transformation. Thus, the development of a siRNA delivery system (DDS) with ultra-stability and specificity is demanded to address the predicament of siRNA delivery.Results: Here, we assembled RNase resistant RNA nanoparticles (NPs) based on the 3WJ of Phi29 DNA packaging motor. To targeted therapy and sensitize TNBC to chemotherapy, the RNA NPs were equipped with epidermal growth factor receptor (EGFR) targeting aptamer and XBP1 siRNA. We found our RNA NPs could deplete XBP1 expression and suppress tumor growth after intravenous administration. Meanwhile, RNA NPs treatment could promote the sensitization of chemotherapy and impair angiogenesis in vivo. Conclusions: The results further demonstrate that our RNA NPs could serve as an effective and promising platform not only for siRNA delivery but also for chemotherapy-resistant TNBC therapy.

scholarly journals Role of TSP-1 as prognostic marker in various cancers: a systematic review and meta-analysis

2020 ◽  
Author(s):  
Shengjie Sun ◽  
Huiyu Dong ◽  
Tao Yan ◽  
Junchen Li ◽  
Chao Liang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Poor Prognosis ◽  
Meta Analysis ◽  
Gynecological Cancer ◽  
Disease Free Survival ◽  
Progression Free Survival ◽  
Cochrane Library ◽  
Poor Overall Survival ◽  
Free Survival ◽  
The Impact

Abstract Background Published studies present conflicting data regarding the impact of Thrombospondin-1 (TSP-1) expression on prognosis of various cancers . We performed this meta-analysis to clarify the preliminary predictive value of TSP-1. Methods Twenty-four studies with a total of 2379 patients were included. A comprehensive literature search was performed by using PubMed, Cochrane Library, Web of Science, Embase, and hand searches were also conducted of relevant bibliographies. Pooled hazard ratio s ( HRs ) with 95% confidence intervals ( CIs ) for patient survival and disease recurrence were initially identified to explore relationships between TSP-1 expression and patient prognosis. Results A total of 24 eligible studies were included in this meta-analysis. Our results showed that high level of TSP-1 was correlated significantly with poor overall survival ( OS ) (HR=1.40, 95% CI: 1.17~1.68). However, high TSP-1 expression predicted no significant impact on progression-free survival ( PFS )/ metastasis-free survival (MFS ) (HR=1.35, 95%CI: 0.87-2.10) and disease-free survival ( DFS )/ recurrence-free survival ( RFS ) (HR = 1.40, 95%CI: 0.77–2.53). In addition, we performed subgroup analyses which showed that high TSP-1 expression predicted poor prognosis in breast cancer and gynecological cancer. Conclusions Our findings indicated high TSP-1 expression may serve as a promising biomarker of poor prognosis and novel therapeutic target in cancers, especially in breast cancer and gynecological cancer.

scholarly journals Hyperinsulinemia promotes aberrant histone acetylation in triple negative breast cancer

2018 ◽  
Author(s):  
Parijat Senapati ◽  
Christine Thai ◽  
Angelica Sanchez ◽  
Emily J Gallagher ◽  
Derek LeRoith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Histone Acetylation ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Prognostic Indicator ◽  
Gene Promoters ◽  
Genome Wide ◽  
Altered Gene ◽  
The Impact

AbstractExcess levels of insulin relative to glucose in the blood, or hyperinsulinemia, is considered to be a poor prognostic indicator for patients with triple negative breast cancer (TNBC). While this association has been recognized for some time, the mechanistic role of hyperinsulinemia in promoting TNBC remains unclear. We show that insulin treatment leads to genome-wide increase in histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway in MDA-MB-231 cells. Genome-wide analysis showed that the increase in histone acetylation occurs primarily at gene promoters. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells. In vivo, hyperinsulinemia also enhances growth of MDA-MB-231 derived tumors through increased histone acetylation. These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC.

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