scholarly journals Patient-derived triple negative breast cancer organoids provide robust model systems that recapitulate tumor intrinsic characteristics

2021 ◽  
Author(s):  
Sonam Bhatia ◽  
Melissa Kramer ◽  
Suzanne Russo ◽  
Payal Naik ◽  
Gayatri Arun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Cancer Biology ◽  
Triple Negative ◽  
Treatment Options ◽  
Cell Types ◽  
Model Systems ◽  
Breast Cancers ◽  
Robust Model

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with poor patient outcomes, and an unmet clinical need for targeted therapies and better model systems. Here, we developed and comprehensively characterized a diverse biobank of normal and breast cancer patient-derived organoids (PDOs) with a focus on TNBCs. PDOs recapitulated patient tumor intrinsic properties and a subset of PDOs can be propagated for long-term culture (LT-TNBCs). Single cell profiling of PDOs identified cell types and gene candidates affiliated with different aspects of cancer progression. The LT-TNBC organoids exhibit signatures of aggressive MYC-driven basal-like breast cancers and are largely comprised of luminal progenitor (LP)-like cells. The TNBC LP-like cells are distinct from normal LPs and exhibit hyperactivation of NOTCH and MYC signaling. Overall, our study validates TNBC PDOs as robust models for understanding breast cancer biology and progression, paving the way for personalized medicine and better treatment options.

Claudin 1, 3, 4, and 7 expression in triple-negative breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1070-1070
Author(s):  
Beom Seok Ko ◽  
Hee Jeong Kim ◽  
Jong Han Yu ◽  
jong Won Lee ◽  
Byung Ho Sohn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Disease Free Survival ◽  
Endocrine Treatment ◽  
Lymph Node Status ◽  
High Recurrence Rate ◽  
Breast Cancers

1070 Background: Triple negative breast cancer (TNBC) often grows rapidly and has poor prognosis, with a high recurrence rate. Because conventional endocrine treatment and HER2 targeted therapy for TNBC is invalid, chemotherapy is the only systemic treatment for TNBC. It is known that several subtypes within the TNBC show different responses to chemotherapy, depending on the subtypes. Recently, a claudin (CLDN) low breast cancer has been identified, exhibiting low expressions of CLDNs 1, 3, 4 and 7. CLDNs are transmembrane proteins that seal tight junctions and are critical for maintaining cell-to-cell adhesion in epithelial cell sheets. However, their role in cancer progression remains largely unexplored. Methods: Surgically removed, formalin-fixed, paraffin-embedded breast cancers from 341 TNBC patients were analyzed to identify CLDN expression.They underwent wide local excision or mastectomy between March, 2004 and December, 2007 at the breast surgery unit of Asan Medical Central Hospital. Results: In our tumor series, we found 45.0% (153/339) of high expressing cases for CLDN1, 57.0% (192/337) for CLDN3, 57.6% (194/337) for CLDN4 and 44.0% (149/339) for CLDN7. Overall, we found 20.5% (70/341) of cases were within the low CLDN expression group and 79.5% (271/341) of tumors were within the high expression group of CLDN1, 3, 4 ,7. Although the high CLDN expression group was significantly associated with positive lymph node status and higher stage, there were no significant differences between CLDN low and high groups in disease free survival (p=0.477) or overall survival (p=0.253). Conclusions: CLDN high tumors are associated with poor prognosis features, but they are not an independent prognostic factor in TNBC patients. However, the mechanisms underlying the different roles of CLDNs in tumorigenesis are largely unclear. Studying the associations of these CLDNs with the TNBC subgroup of breast cancers might provide us with potential diagnostic biomarkers or therapeutic targets for cancer cells.

scholarly journals A paclitaxel and microRNA-124 coloaded stepped cleavable nanosystem against triple negative breast cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Chuanrong Chen ◽  
Ming Shen ◽  
Hongze Liao ◽  
Qianqian Guo ◽  
Hao Fu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Disulfide Bonds ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Treatment Options ◽  
Breast Cancers ◽  
Mesenchymal Transition ◽  
Tumour Metastasis ◽  
Microrna 124

Abstract Background Triple negative breast cancer (TNBC) is one of the most biologically aggressive breast cancers and lacks effective treatment options, resulting in a poor prognosis. Therefore, studies aiming to explore new therapeutic strategies for advanced TNBC are urgently needed. According to recent studies, microRNA-124 (miR124) not only inhibits tumour growth but also increases the sensitivity of TNBC to paclitaxel (PTX), suggesting that a platform combining PTX and miR124 may be an advanced solution for TNBC. Results Herein, we constructed a stepped cleavable calcium phosphate composite lipid nanosystem (CaP/LNS) to codeliver PTX and miR124 (PTX/miR124-NP). PTX/miR124-NP exhibited superior tumor microenvironment responsive ability, in which the surface PEG layer was shed in the mildly acidic environment of tumor tissues and exposed oligomeric hyaluronic acid (o-HA) facilitated the cellular uptake of CaP/LNS by targeting the CD44 receptor on the surface of tumor cells. Inside tumour cells, o-HA detached from CaP/LNS due to the reduction of disulfide bonds by glutathione (GSH) and inhibited tumour metastasis. Then, PTX and miR124 were sequentially released from CaP/LNS and exerted synergistic antitumour effects by reversing the Epithelial-Mesenchymal Transition (EMT) process in MDA-MB-231 cells. Moreover, PTX/miR124-NP showed significant antitumour efficiency and excellent safety in mice bearing MDA-MB-231 tumours. Conclusion Based on these results, the codelivery of PTX and miR124 by the CaP/LNS nanosystem might be a promising therapeutic strategy for TNBC.

scholarly journals Current and emerging treatment options in triple-negative breast cancer

2011 ◽  
Vol 4 (1) ◽  
pp. 5
Author(s):  
Omer Dizdar ◽  
Kadri Altundag
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Histological Grade ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Immunohistochemical Analysis ◽  
Endocrine Treatment ◽  
Breast Cancers ◽  
Chemotherapy Drugs

Triple-negative breast cancer is defined by the lack of estrogen receptor, progesterone receptor and HER2 expression with immunohistochemical analysis. Triplenegative breast cancers are poorly differentiated, characterized by high histological grade and occur at a younger age. Treatment options are limited as these tumors are naturally resistant to existing targeted therapies, i.e., endocrine treatment and trastuzumab. An improved understanding of the biology of TNBC has led to evaluation of DNA-damaging chemotherapy drugs and targeted agents, including poly (ADP-ribose) polymerase inhibitors, epidermal growth factor receptor inhibitors, angiogenesis inhibitors, etc., in the treatment of TNBC. This review focuses on outlining the current and emerging treatment options in patients with triple-negative breast cancer.

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.

Triple Negative Breast Cancer Pathologic Diagnosis and Current Chemotherapy Treatment Options

2014 ◽  
Vol 10 (01) ◽  
pp. 35 ◽  
Author(s):  
Bernardo L Rapoport ◽  
Simon Nayler ◽  
Georgia S Demetriou ◽  
Shun D Moodley ◽  
Carol A Benn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Treatment Options ◽  
Single Agent ◽  
Metastatic Breast ◽  
Complete Response ◽  
Breast Cancers ◽  
Metastatic Setting

Triple negative breast cancer (TNBC) comprises 12–20 % of all breast cancers and are a heterogeneous group of tumours, both clinically and pathologically. These cancers are characterised by the lack of expression of the hormone receptors oestrogen receptor (OR) and progesterone receptor (PR), combined with the lack of either overexpression or amplification of the human epidermal growth factor receptor-2 (HER2) gene. Conventional cytotoxic chemotherapy and DNA damaging agents continue to be the mainstay of treatment of this disease in the neoadjuvant, adjuvant and metastatic setting. The lack of predictive markers in identifying potential targets for the treatment of TNBC has left a gap in directed therapy in these patients. Platinum agents have seen renewed interest in TNBC based on an increasing body of preclinical and clinical data suggesting encouraging activity. However, comparisons between chemotherapy regimens are mostly retrospective in nature and the best agents or drug combinations for TNBC have not been established in prospective randomised trials. Numerous studies have now shown that TNBC has significantly higher pathological complete response (pCR) rates compared with hormone receptor positive breast cancer when treated with neoadjuvant chemotherapy, and pCR correlates well with better outcomes for these patients. Patients with TNBC account for a larger number of deaths in the setting of metastatic breast cancer. There is no preferred treatment for the first-line metastatic setting. Although individual agents are recommended, given the often aggressive nature of TNBC and the presence of extensive visceral disease, the use of a combination of drugs, rather than a single agent, is often advocated. This review article will outline the pathological diagnosis of TNBC and the treatment options available to these patients in the neoadjuvant, adjuvant and metastatic setting, including an assessment of future directions of treatment.

scholarly journals Response to Vemurafenib in Metastatic Triple-Negative Breast Cancer Harbouring a BRAF V600E Mutation: A Case Report and Electronically Captured Patient-Reported Outcome

2021 ◽  
pp. 616-621
Author(s):  
Magdalena Pircher ◽  
Thomas Winder ◽  
Andreas Trojan
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Braf Inhibitor ◽  
Local Therapy ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Breast Cancers ◽  
Patient Reported

Effective treatment options are still scarce for metastatic triple-negative breast cancers. An increasing interest in the mutational landscape of this disease will facilitate novel therapeutic strategies in a variety of cancers. Here we report the case of a 38-year-old female patient who developed multiple lung metastasis of a triple-negative breast cancer 2 years after the completion of local therapy. When she progressed after two palliative chemotherapy lines and local electroporation, a next-generation sequencing revealed a BRAF V600E mutation for which we initiated therapy with the BRAF inhibitor vemurafenib. Radiological improvement was already evident after 3 months and has been ongoing for 19 months so far with very few side effects, as is demonstrated by electronically captured patient-reported outcomes. To our knowledge, this is the first published case where a BRAF V600E-mutated advanced triple-negative breast cancer was successfully treated with vemurafenib.

scholarly journals Current and emerging treatment options in triple-negative breast cancer

2011 ◽  
pp. 5-13
Author(s):  
Omer Dizdar ◽  
Kadri Altundag
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Histological Grade ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Immunohistochemical Analysis ◽  
Endocrine Treatment ◽  
Breast Cancers ◽  
Chemotherapy Drugs

Triple-negative breast cancer is defined by the lack of estrogen receptor, progesterone receptor and HER2 expression with immunohistochemical analysis. Triplenegative breast cancers are poorly differentiated, characterized by high histological grade and occur at a younger age. Treatment options are limited as these tumors are naturally resistant to existing targeted therapies, i.e., endocrine treatment and trastuzumab. An improved understanding of the biology of TNBC has led to evaluation of DNA-damaging chemotherapy drugs and targeted agents, including poly (ADP-ribose) polymerase inhibitors, epidermal growth factor receptor inhibitors, angiogenesis inhibitors, etc., in the treatment of TNBC. This review focuses on outlining the current and emerging treatment options in patients with triple-negative breast cancer.

NFKBIA deletion in triple-negative breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1012-1012 ◽  
Author(s):  
Markus Bredel ◽  
Hyunsoo Kim ◽  
Nanda K. Thudi ◽  
Denise M. Scholtens ◽  
James A. Bonner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Target Genes ◽  
Triple Negative ◽  
Lung Metastases ◽  
Treatment Options ◽  
Underlying Mechanism ◽  
Breast Cancers ◽  
Suppressor Activity ◽  
Free Survival

1012 Background: While effective, target-directed therapies are available for ER-positive and HER2-amplified breast cancer, adjuvant therapeutic options for triple-negative breast cancer (TNBC) are limited in the absence of well-defined molecular targets. Constitutive activation of oncogenic nuclear factor kB (NFkB) has been associated with ER-negative or basal-like (BL) breast cancers, but the underlying mechanism of this activation remains undefined. We previously showed that deletion of the endogenous NFkB repressor gene NFKBIA associates with EGFR non-amplified glioblastoma multiforme and portends unfavorable clinical outcome (Bredel et al. NEJM 2011). Methods: We analyzed >5,000 human breast cancers for deletions, mutations and/or expression of NFKBIA. We studied tumor suppressor activity of NFKBIA and the effect of targeted NFkB inhibition in cell culture with various NFKBIA genotypes. We compared molecular results with outcomes of affected persons. Results: NFKBIA is often (10.8%) deleted but not mutated in breast cancer. NFKBIA deletions are significantly associated with TNBC (32.8%) and particularly frequent in the BL subtype (36.7%). Loss of NFKBIA exerts a haploinsufficient effect on NFKBIA expression and the transactivation of several NF-kB target genes with important roles in breast carcinogenesis. Restoration of NFKBIA expression or pharmacologic NFkB inhibition attenuates the malignant phenotype of cells cultured from TNBC with NFKBIA deletion. Deletion and low expression of NFKBIA are highly associated with unfavorable overall survival, independent of patient age, tumor stage, nodal status, and tumor subtype. Loss of NFKBIA expression portends significantly poorer disease-specific survival, recurrence-free survival, and distant metastasis-free survival. Moreover, NFKBIA expression is significantly associated with duration of metastasis-free survival in subgroups of patients with brain or lung metastases from breast cancer. Conclusions: NFKBIA is a new, prognostically relevant, molecular target in TNBC, which remains a clinically challenging subtype of breast cancer with limited treatment options.

scholarly journals Triple-negative breast cancer: challenges and treatment options

2020 ◽  
Vol 11 (2) ◽  
pp. 1977-1986
Author(s):  
Nithish Shekar ◽  
Pooja Mallya ◽  
D V Gowda ◽  
Vikas Jain
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Triple Negative Breast Cancer ◽  
Biological Diversity ◽  
Triple Negative ◽  
Treatment Options ◽  
Breast Cancers ◽  
Continuous Progress ◽  
Epithelial Growth

TNBCs or Triple negative breast cancers are characterized by the deficiency of progesterone and estrogen receptors and also the absence down regulation of Human epithelial growth receptor type 2 (HER2). TNBCs have low prognosis rate because of heterogeneity.The heterogeneous nature of this cancer has constrained the effective progress in drug targeting among certain people.. In general HER2, PR and ER and the rate of proliferation are main predictive and prognostic factors in the detection of cancer of breast.Several pathways are involved in the progression of triple negative breast cancer from basal like cancer cells. The foremost being the loss by BRCA1-mediated pathway or mutation in the expression of several receptors.Certain groups have made some progress in unwinding TNBC's biological diversity and relating patterns of gene expression to molecular or genotypic subtypes.Earlier molecular categories of breast cancer use PAM50 via gene expression analysis to separate the breast cancer into the 4 intrinsic subtypes classified among many TNBCs in basal (BL) group and others divided between HER2 and luminal rich group. Currently, targeted therapy for TNBCs has not been approved. Nonetheless, a continuous progress has been made to detect the tumors at specific site for targeting and establish novel improved therapy.This review speaks about different approaches to TNBC treatment like cytotoxic therapy, targeted strategies, and chemotherapeutics by damage to DNA and targeting for repair of DNA and potent Nano carriers for targeting TNBC.

scholarly journals Triple Negative Breast Cancer—Review of Current and Emerging Therapeutic Strategies

2016 ◽  
Vol 12 (02) ◽  
pp. 89 ◽  
Author(s):  
Tarah Ballinger ◽  
Jill Kremer ◽  
Kathy Miller ◽  
◽  
◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Current Treatment ◽  
Tumor Type ◽  
Breast Cancers ◽  
Brca Mutations ◽  
Tumor Subtypes ◽  
Cancer Review

Triple negative breast cancer (TNBC) is associated with a poor prognosis compared to other types of breast cancer. The classification of ‘triple negative’ is not one homogenous tumor type, but rather is made up of multiple molecularly and biologically diverse tumor subtypes. At present, no approved targeted therapy exists and the standard remains cytotoxic chemotherapy. The identification of TNBC subtypes has provided a basis for identifying possible targeted therapeutic options. In addition, the recognition that some TNBCs share characteristics similar to tumors arising in patients with germline BRCA mutations has led to consideration of DNA damaging agents as a potential treatment option. Multiple investigational approaches are also underway, including immune checkpoint inhibition, poly (ADP-ribose) polymerase inhibition, and androgen receptor blockage. The limited options available for systemic treatment of TNBC will hopefully expand as more is learned about the complex biology and molecular targets of this group of breast cancers. This review will discuss the biology of TNBC, current treatment options, and promising experimental strategies.

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