scholarly journals Honeybee venom and melittin suppress growth factor receptor activation in HER2-enriched and triple-negative breast cancer

2020 ◽  
Vol 4 (1) ◽  
Author(s):  
Ciara Duffy ◽  
Anabel Sorolla ◽  
Edina Wang ◽  
Emily Golden ◽  
Eleanor Woodward ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Plasma Membrane ◽  
Anticancer Agents ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Treatment Strategies ◽  
Receptor Activation ◽  
Breast Cancers ◽  
Honeybee Venom ◽  
Cancer Subtypes

Abstract Despite decades of study, the molecular mechanisms and selectivity of the biomolecular components of honeybee (Apis mellifera) venom as anticancer agents remain largely unknown. Here, we demonstrate that honeybee venom and its major component melittin potently induce cell death, particularly in the aggressive triple-negative and HER2-enriched breast cancer subtypes. Honeybee venom and melittin suppress the activation of EGFR and HER2 by interfering with the phosphorylation of these receptors in the plasma membrane of breast carcinoma cells. Mutational studies reveal that a positively charged C-terminal melittin sequence mediates plasma membrane interaction and anticancer activity. Engineering of an RGD motif further enhances targeting of melittin to malignant cells with minimal toxicity to normal cells. Lastly, administration of melittin enhances the effect of docetaxel in suppressing breast tumor growth in an allograft model. Our work unveils a molecular mechanism underpinning the anticancer selectivity of melittin, and outlines treatment strategies to target aggressive breast cancers.

scholarly journals Identification of Long Noncoding RNAs as Predictors of Survival in Triple-Negative Breast Cancer Based on Network Analysis

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Xiao-Xiao Li ◽  
Li-Juan Wang ◽  
Jie Hou ◽  
Hong-Yang Liu ◽  
Rui Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Network Analysis ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Breast Cancers ◽  
Luminal A ◽  
Her2 Positive ◽  
Cancer Subtypes

Breast cancer is the most common cancer observed in adult females, worldwide. Due to the heterogeneity and varied molecular subtypes of breast cancer, the molecular mechanisms underlying carcinogenesis in different subtypes of breast cancer are distinct. Recently, long noncoding RNAs (lncRNAs) have been shown to be oncogenic or play important roles in cancer suppression and are used as biomarkers for diagnosis and therapy. In this study, we identified 134 lncRNAs and 6,414 coding genes were differentially expressed in triple-negative (TN), human epidermal growth factor receptor 2- (HER2-) positive, luminal A-positive, and luminal B-positive breast cancer. Of these, 37 lncRNAs were found to be dysregulated in all four subtypes of breast cancers. Subtypes of breast cancer special modules and lncRNA-mRNA interaction networks were constructed through weighted gene coexpression network analysis (WGCNA). Survival analysis of another public datasets was used to verify the identified lncRNAs exhibiting potential indicative roles in TN prognosis. Results from heat map analysis of the identified lncRNAs revealed that five blocks were significantly displayed. High expressions of lncRNAs, including LINC00911, CSMD2-AS1, LINC01192, SNHG19, DSCAM-AS1, PCAT4, ACVR28-AS1, and CNTFR-AS1, and low expressions of THAP9-AS1, MALAT1, TUG1, CAHM, FAM2011, NNT-AS1, COX10-AS1, and RPARP-AS1 were associated with low survival possibility in TN breast cancers. This study provides novel lncRNAs as potential biomarkers for the therapeutic and prognostic classification of different breast cancer subtypes.

Q-CROC-03: A prospective biopsy driven clinical trial to study the mechanisms of resistance to chemotherapy in triple-negative breast cancer patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS1139-TPS1139
Author(s):  
Adriana Aguilar-Mahecha ◽  
Josiane Lafleur ◽  
Carole Seguin ◽  
Catalin Liviu Dragos Mihalcioiu ◽  
Josee-Anne Roy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Limiting Factors ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Tumor Resistance ◽  
Cancer Subtypes ◽  
Resistance To Chemotherapy

TPS1139 Background: Resistance to chemotherapy or targeted agents is the cause of death in most patients dying of breast cancer and one of the major challenges presently faced by oncologists. In triple negative breast cancers (TNBCs), drug resistance emerges quicker than in other breast cancer subtypes and contributes to the poor prognosis seen in these patients. The lack of targeted therapies to treat TNBC highlights the important need to better understand the molecular mechanisms contributing to chemotherapy resistance in order to develop new therapeutic strategies. However, the difficulty in obtaining tissue samples from drug resistant tumors has been one of the limiting factors in this field of study. Methods: We have designed a prospective phase II clinical trial where paired biopsies are collected from chemotherapy resistant TNBCs (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. Metastatic sites eligible for biopsy include liver, lung, skin and lymph nodes. This study is presently recruiting at 5 major health centers in Quebec and will soon open in the USA. We have currently enrolled 13 patients in the neoadjuvant setting and 2 metastatic patients. Major challenges in patient enrolment will be discussed. 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. 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. Collection of clinical data will allow molecular profiling data to be linked to clinical response data so as to determine DNA, RNA and protein factors correlated with tumor resistance to chemotherapy.

scholarly journals Cisplatin-resistant triple-negative breast cancer subtypes: multiple mechanisms of resistance

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
David P. Hill ◽  
Akeena Harper ◽  
Joan Malcolm ◽  
Monica S. McAndrews ◽  
Susan M. Mockus ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Treatment Strategies ◽  
Heterogeneous Data ◽  
Variable Response ◽  
Mechanisms Of Resistance ◽  
Mesenchymal Transition ◽  
Cancer Subtypes

Abstract Background Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. For example, triple-negative breast cancer (TNBC) patients have variable response to the chemotherapeutic agent cisplatin. Understanding the basis of treatment response in cancer subtypes will lead to more informed decisions about selection of treatment strategies. Methods In this study we used an integrative functional genomics approach to investigate the molecular mechanisms underlying known cisplatin-response differences among subtypes of TNBC. To identify changes in gene expression that could explain mechanisms of resistance, we examined 102 evolutionarily conserved cisplatin-associated genes, evaluating their differential expression in the cisplatin-sensitive, basal-like 1 (BL1) and basal-like 2 (BL2) subtypes, and the two cisplatin-resistant, luminal androgen receptor (LAR) and mesenchymal (M) subtypes of TNBC. Results We found 20 genes that were differentially expressed in at least one subtype. Fifteen of the 20 genes are associated with cell death and are distributed among all TNBC subtypes. The less cisplatin-responsive LAR and M TNBC subtypes show different regulation of 13 genes compared to the more sensitive BL1 and BL2 subtypes. These 13 genes identify a variety of cisplatin-resistance mechanisms including increased transport and detoxification of cisplatin, and mis-regulation of the epithelial to mesenchymal transition. Conclusions We identified gene signatures in resistant TNBC subtypes indicative of mechanisms of cisplatin. Our results indicate that response to cisplatin in TNBC has a complex foundation based on impact of treatment on distinct cellular pathways. We find that examination of expression data in the context of heterogeneous data such as drug-gene interactions leads to a better understanding of mechanisms at work in cancer therapy response.

scholarly journals Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4139
Author(s):  
Pere Llinàs-Arias ◽  
Sandra Íñiguez-Muñoz ◽  
Kelly McCann ◽  
Leonie Voorwerk ◽  
Javier I. J. Orozco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Regulatory Elements ◽  
Her2 Overexpression ◽  
Breast Cancers ◽  
Cancer Subtypes

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments.

scholarly journals Cis-Compound Mutations are Prevalent in Triple Negative Breast Cancer and Can Drive Tumor Progression

2016 ◽  
Author(s):  
Nao Hiranuma ◽  
Jie Liu ◽  
Chaozhong Song ◽  
Jacob Goldsmith ◽  
Michael Dorschner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative ◽  
The Cancer Genome Atlas ◽  
Breast Cancers ◽  
Single Nucleotide Variants ◽  
Primary Tumors ◽  
Cancer Subtypes ◽  
Multiple Biopsies ◽  
Cancer Genome Atlas

About 16% of breast cancers fall into a clinically aggressive category designated triple negative (TNBC) due to a lack of ERBB2, estrogen receptor and progesterone receptor expression1-3. The mutational spectrum of TNBC has been characterized as part of The Cancer Genome Atlas (TCGA)4; however, snapshots of primary tumors cannot reveal the mechanisms by which TNBCs progress and spread. To address this limitation we initiated the Intensive Trial of OMics in Cancer (ITOMIC)-001, in which patients with metastatic TNBC undergo multiple biopsies over space and time5. Whole exome sequencing (WES) of 67 samples from 11 patients identified 426 genes containing multiple distinct single nucleotide variants (SNVs) within the same sample, instances we term Multiple SNVs affecting the Same Gene and Sample (MSSGS). We find that >90% of MSSGS result from cis-compound mutations (in which both SNVs affect the same allele), that MSSGS comprised of SNVs affecting adjacent nucleotides arise from single mutational events, and that most other MSSGS result from the sequential acquisition of SNVs. Some MSSGS drive cancer progression, as exemplified by a TNBC driven by FGFR2(S252W;Y375C). MSSGS are more prevalent in TNBC than other breast cancer subtypes and occur at higher-than-expected frequencies across TNBC samples within TCGA. MSSGS may denote genes that play as yet unrecognized roles in cancer progression.

scholarly journals P-Rex1 Expression in Invasive Breast Cancer in relation to Receptor Status and Distant Metastatic Site

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Jonathan D. Marotti ◽  
Kristen E. Muller ◽  
Laura J. Tafe ◽  
Eugene Demidenko ◽  
Todd W. Miller
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Breast Tumors ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Solid Organ ◽  
Breast Cancers ◽  
Primary Tumors ◽  
Receptor Status ◽  
Cancer Subtypes

Background. Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1 (P-Rex1) has been implicated in cancer growth, metastasis, and response to phosphatidylinositol 3-kinase (PI3K) inhibitor therapy. The aim of this study was to determine whether P-Rex1 expression differs between primary and metastatic human breast tumors and between breast cancer subtypes. Design. P-Rex1 expression was measured in 133 specimens by immunohistochemistry: 40 and 42 primary breast tumors from patients who did versus did not develop metastasis, respectively, and 51 breast-derived tumors from metastatic sites (36 of which had matching primary tumors available for analysis). Results. Primary breast tumors showed significant differences in P-Rex1 expression based on receptor subtype. ER+ and HER2+ primary tumors showed higher P-Rex1 expression than primary triple-negative tumors. HER2+ metastases from all sites showed significantly higher P-Rex1 expression compared to other metastatic receptor subtypes. Solid organ (i.e., brain, lung, and liver) metastases showed higher P-Rex1 expression compared to bone metastases. Conclusions. P-Rex1 expression is increased in ER+ and HER2+ breast cancers compared to triple-negative tumors. P-Rex1 may be differentially expressed in metastatic tumors based on site and receptor status. The role of P-Rex1 in the development of breast cancer metastases and as a predictive biomarker of therapeutic response warrants further investigation.

scholarly journals Metabolic Syndrome and Triple-Negative Breast Cancer: A New Paradigm

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Andrew A. Davis ◽  
Virginia G. Kaklamani
Keyword(s):  
Breast Cancer ◽  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Growth Factor ◽  
Triple Negative ◽  
Growth Factor Receptor ◽  
Breast Cancers ◽  
New Paradigm ◽  
Cancer Subtypes ◽  
The Metabolic Syndrome

Triple-negative breast cancers (TNBCs) are aggressive tumors with poor prognosis compared to other breast cancer subtypes. The evidence linking TNBC with the metabolic syndrome, which consists of central obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, and hypertension, has emerged from clinical studies and experiments using cell lines and mouse models. Epidemiological studies have associated abdominal obesity with increased incidence of TNBC. Additionally, insulin resistance, dyslipidemia, and hypertension are associated with increased incidence of breast cancer across all subtypes. The insulin-leptin-adiponectin axis has been implicated mechanistically in breast cancer tumorigenesis. Specifically, increased leptin and decreased adiponectin levels disrupt homeostatic signaling pathways involved in cell proliferation, survival, cell-cycle regulation, and angiogenesis. Insulin, insulin-like growth factor I (IGF-I), and epidermal growth factor receptor (EGFR) may mediate interactions between these two hormones. Further research will facilitate the development of targeted therapeutics and programs to modify lifestyle factors to modulate the insulin-leptin-adiponectin axis for TNBC.

scholarly journals Optical Redox Imaging Differentiates Triple-Negative Breast Cancer Subtypes

2021 ◽  
pp. 253-258
Author(s):  
Jinxia Jiang ◽  
Min Feng ◽  
Annemarie Jacob ◽  
Lin Z. Li ◽  
He N. Xu
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Response Patterns ◽  
Breast Cancers ◽  
Cancer Subtypes ◽  
Mitochondrial Inhibitors ◽  
Tnbc Cell

AbstractTriple-negative breast cancer (TNBC) is a highly diverse group of cancers with limited treatment options, responsible for about 15% of all breast cancers. TNBC cells differ from each other in many ways such as gene expression, metabolic activity, tumorigenicity, and invasiveness. Recently, many research and clinical efforts have focused on metabolically targeted therapy for TNBC. Metabolic characterization of TNBC cell lines can facilitate the assessment of therapeutic effects and assist in metabolic drug development. Herein, we used optical redox imaging (ORI) techniques to characterize TNBC subtypes metabolically. We found that various TNBC cell lines had differing redox statuses (levels of reduced nicotinamide adenine dinucleotide (NADH), oxidized flavin adenine dinucleotide (FAD), and the redox ratio (FAD/(NADH+FAD)). We then metabolically perturbed the cells with mitochondrial inhibitors and an uncoupler and performed ORI accordingly. As expected, we observed that these TNBC cell lines had similar response patterns to the metabolic perturbations. However, they exhibited differing redox plasticity. These results suggest that subtypes of TNBC cells are different metabolically and that ORI can serve as a sensitive technique for the metabolic profiling of TNBC cells.

scholarly journals Early Triple Negative Breast Cancer: Conventional Treatment and Emerging Therapeutic Landscapes

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 819 ◽  
Author(s):  
Anna Diana ◽  
Francesca Carlino ◽  
Elisena Franzese ◽  
Olga Oikonomidou ◽  
Carmen Criscitiello ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Residual Disease ◽  
Early Stage ◽  
Treatment Options ◽  
Parp Inhibitors ◽  
Cytotoxic Agents ◽  
Breast Cancers ◽  
Current Standard ◽  
Cancer Subtypes

Triple negative breast cancers (TNBCs) are characterized by worse prognosis, higher propensity to earlier metastases, and shorter survival after recurrence compared with other breast cancer subtypes. Anthracycline- and taxane-based chemotherapy is still the mainstay of treatment in early stages, although several escalation approaches have been evaluated to improve survival outcomes. The addition of platinum salts to standard neoadjuvant chemotherapy (NACT) remains controversial due to the lack of clear survival advantage, and the use of adjuvant capecitabine represents a valid treatment option in TNBC patients with residual disease after NACT. Recently, several clinical trials showed promising results through the use of poly ADP-ribose polymerase (PARP) inhibitors and by incorporating immunotherapy with chemotherapy, enriching treatment options beyond conventional cytotoxic agents. In this review, we provided an overview on the current standard of care and a comprehensive update of the recent advances in the management of early stage TNBC and focused on the latest emerging biomarkers and their clinical application to select the best therapeutic strategy in this hard-to-treat population.

scholarly journals Blood Genome-Wide Transcriptional Profiles of HER2 Negative Breast Cancers Patients

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Ovidiu Balacescu ◽  
Loredana Balacescu ◽  
Oana Virtic ◽  
Simona Visan ◽  
Claudia Gherman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative ◽  
Transcriptional Analysis ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Primary Tumors ◽  
Cancer Subtypes ◽  
Her2 Breast Cancer ◽  
Adaptive Immune Cells

Tumors act systemically to sustain cancer progression, affecting the physiological processes in the host and triggering responses in the blood circulating cells. In this study, we explored blood transcriptional patterns of patients with two subtypes of HER2 negative breast cancers, with different prognosis and therapeutic outcome. Peripheral blood samples from seven healthy female donors and 29 women with breast cancer including 14 triple-negative breast cancers and 15 hormone-dependent breast cancers were evaluated by microarray. We also evaluated the stroma in primary tumors. Transcriptional analysis revealed distinct molecular signatures in the blood of HER2− breast cancer patients according to ER/PR status. Our data showed the implication of immune signaling in both breast cancer subtypes with an enrichment of these processes in the blood of TNBC patients. We observed a significant alteration of “chemokine signaling,” “IL-8 signaling,” and “communication between innate and adaptive immune cells” pathways in the blood of TNBC patients correlated with an increased inflammation and necrosis in their primary tumors. Overall, our data indicate that the presence of triple-negative breast cancer is associated with an enrichment of altered systemic immune-related pathways, suggesting that immunotherapy could possibly be synergistic to the chemotherapy, to improve the clinical outcome of these patients.

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