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Fulltext 2-Methoxy-1,4-Naphthoquinone (MNQ) Inhibits Glucose Uptake and Lactate Production in Triple-Negative Breast Cancer Cells

Daud SM, Yaacob NS, Fauzi AN

Asian Pac J Cancer Prev, 2021 Feb 01;22(S1):59-65.
PMID: 33576213 DOI: 10.31557/APJCP.2021.22.S1.59

OBJECTIVE: The persistent activation of aerobic glycolysis in cancer cells results in accumulation of lactate and other metabolic intermediates that contribute to tumorigenesis. Increased glycolysis is frequently dysregulated in triple-negative breast cancer (TNBC), which promotes tumor growth and immune escape. This study was conducted to investigate the effect of 2-methoxy-1, 4-naphthoquinone (MNQ), compound extracted from Impatiens balsamina on glycolytic activities in human breast adenocarcinoma, MDA-MB-231 cells.
METHODS: Initially, MTT proliferation assay was used to test the cell viability with various doses of MNQ (5-100 µM). As the half maximal inhibitory concentration (IC50) was obtained, glucose uptake and lactate assays of the cells were tested with IC50 dose of MNQ. The treated cells were also subjected to gene and protein analysis of glycolysis-related molecules (GLUT1 and Akt).
RESULTS: The results showed that MNQ decreased the percentage of MDA-MB-231 cell viability in a dose-dependent manner with the IC50 value of 29 µM. The percentage of glucose uptake into the cells and lactate production decreased significantly after treatment with MNQ as compared to untreated cells. Remarkably, the expressions of GLUT1 and Akt molecules decreased in MNQ-treated cells, suggesting that the inhibition of glycolysis by MNQ is GLUT1-dependent and possibly mediated by the Akt signaling pathway.
CONCLUSION: Our findings indicate the ability of MNQ to inhibit the glycolytic activities as well as glycolysis-related molecules in MDA-MB-231 cells, suggesting the potential of MNQ to be further developed as an effective anticancer agent against TNBC cells.

Matched MeSH terms: Triple Negative Breast Neoplasms/drug therapy*; Triple Negative Breast Neoplasms/metabolism; Triple Negative Breast Neoplasms/pathology
Fulltext A novel 4-arm DNA/RNA Nanoconstruct triggering Rapid Apoptosis of Triple Negative Breast Cancer Cells within 24 hours

Tung J, Tew LS, Hsu YM, Khung YL

Sci Rep, 2017 04 11;7(1):793.
PMID: 28400564 DOI: 10.1038/s41598-017-00912-3

Measuring at ~30 nm, a fully customizable holliday junction DNA nanoconstruct, was designed to simultaneously carry three unmodified SiRNA strands for apoptosis gene knockout in cancer cells without any assistance from commercial transfection kits. In brief, a holliday junction structure was intelligently designed to present one arm with a cell targeting aptamer (AS1411) while the remaining three arms to carry different SiRNA strands by means of DNA/RNA duplex for inducing apoptosis in cancer cells. By carrying the three SiRNA strands (AKT, MDM2 and Survivin) into triple negative breast MDA-MB-231 cancer cells, cell number had reduced by up to ~82% within 24 hours solely from one single administration of 32 picomoles. In the immunoblotting studies, up-elevation of phosphorylated p53 was observed for more than 8 hours while the three genes of interest were suppressed by nearly half by the 4-hour mark upon administration. Furthermore, we were able to demonstrate high cell selectivity of the nanoconstruct and did not exhibit usual morphological stress induced from liposomal-based transfection agents. To the best of the authors' knowledge, this system represents the first of its kind in current literature utilizing a short and highly customizable holliday DNA junction to carry SiRNA for apoptosis studies.

Matched MeSH terms: Triple Negative Breast Neoplasms/genetics*
Fulltext Combined atezolizumab and nab-paclitaxel in the treatment of triple negative breast cancer: a meta-analysis on their efficacy and safety

Sharmni Vishnu K, Win TT, Aye SN, Basavaraj AK

BMC Cancer, 2022 Nov 05;22(1):1139.
PMID: 36335316 DOI: 10.1186/s12885-022-10225-y

BACKGROUND: Triple negative breast cancer (TNBC) is clinically aggressive breast cancer with a poor prognosis. Approximately 20% of TNBC has been found to express programmed death ligand 1 (PD-L1), making it a potential therapeutic target. As a PD-L1 inhibitor, atezolizumab is a recently approved immunotherapeutic drug for TNBC, this meta-analysis (MA) was aimed to review the randomized controlled trial studies (RCTs) of combined atezolizumab and nab-paclitaxel in the treatment of TNBC and synthesize the evidence-based results on its effectiveness and safety.
METHOD: We searched PubMed, Embase, EBSCOhost and ClinicalTrials.gov for the eligible RCTs which compared the efficacy and safety of combined atezolizumab and nab-paclitaxel with nab-paclitaxel alone. The outcomes analyzed included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and treatment-related adverse effects (AEs).
RESULTS: A total of six RCTs were included in this MA. For efficacy, although OS was not significantly prolonged with combined atezolizumab and nab-paclitaxel (HR 0.90, 95% CI [0.79, 1.01], p=0.08), this combination therapy significantly improved PFS (HR 0.72, 95% CI [0.59, 0.87], p=0.0006) and ORR (RR 1.25, 95% CI [0.79, 1.01] p<0.00001). For safety, any AEs, haematological, gastrointestinal, and liver AEs showed no statistically significant differences between the atezolizumab and nab-paclitaxel combination group and nab-paclitaxel alone group. However, serious AEs, high grade, dermatological, pulmonary, endocrine, and neurological AEs were significantly lower with nab-paclitaxel alone compared to atezolizumab and nab-paclitaxel combined (p-value range from <0.00001 to 0,02).
CONCLUSION: Atezolizumab combined with nab-paclitaxel was associated with improved outcomes in the treatment of TNBC; however, this combination resulted in more toxicity compared to nab-paclitaxel alone. While nab-paclitaxel alone produced chemotherapy-related AEs, the combination of atezolizumab with nab-paclitaxel produced AEs, especially immune-related AEs such as haematological, pulmonary, endocrine, and neurological AEs.
TRIAL REGISTRATION: This research work of systematic review has been registered on PROSPERO (Registration number: CRD42022297952).

Matched MeSH terms: Triple Negative Breast Neoplasms*
Fulltext Pitfalls in machine learning-based assessment of tumor-infiltrating lymphocytes in breast cancer: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer

Thagaard J, Broeckx G, Page DB, Jahangir CA, Verbandt S, Kos Z, et al.

J Pathol, 2023 Aug;260(5):498-513.
PMID: 37608772 DOI: 10.1002/path.6155

The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. We categorize our findings into four main topics: (1) technical slide issues, (2) ML and image analysis aspects, (3) data challenges, and (4) validation issues. The main reason for discordant assessments is the inclusion of false-positive areas or cells identified by performance on certain tissue patterns or design choices in the computational implementation. To aid the adoption of ML for TIL assessment, we provide an in-depth discussion of ML and image analysis, including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial and routine clinical management of patients with triple-negative breast cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Matched MeSH terms: Triple Negative Breast Neoplasms*
A Case Report of a Rare ER+, PR- Pure Metaplastic Breast Squamous Cell Carcinoma with HER2 Overexpression

Adam SA, Kamaruddin KN, Abd Shukor N, Abdullah Suhaimi SN, Ismail F, Md Yasin M

Am J Case Rep, 2023 Dec 04;24:e941448.
PMID: 38048289 DOI: 10.12659/AJCR.941448

BACKGROUND Breast squamous cell carcinoma (SCC) is a subtype of metaplastic breast carcinoma (MBC), which is a rare malignancy and accounts for 0.1% of all invasive breast carcinomas. Guidelines on definitive management and treatment of breast SCC are not well established, given its rarity and diverse immunohistochemistry (IHC) profile, and lack of clinical data. Most cases of breast SCC are triple-negative breast cancer - negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). This case report outlines the clinicopathological profile of a pure breast SCC case with a rare IHC profile; HER2 and ER positive. CASE REPORT A 41-year-old woman presented with a right breast mass that had been growing for 2 months. Biopsy confirmed breast SCC, a rare malignancy with IHC profile as follows: HER2 overexpression, ER positive, and PR negative. She underwent neoadjuvant chemotherapy for 3 months followed by right mastectomy with axillary clearance, adjuvant radiotherapy, and oral tamoxifen therapy. Unfortunately, she did not receive anti-HER2 therapy. She developed early locoregional recurrence at 2 months postoperatively, which was treated with excision of the right chest wall and transverse rectus abdominis musculocutaneous (TRAM) flap. She developed liver and lung metastasis and succumbed to her disease at 15 months post-diagnosis. CONCLUSIONS Breast SCC is a rare and aggressive tumor with heterogeneous clinicopathological features. Available guidelines do not outline the definitive treatment for breast SCC, given its rarity and heterogenous IHC profile, leading to a general lack of clinical data. Hence, due to the challenges in managing this rare condition, treatment modalities need to be individualized.

Matched MeSH terms: Triple Negative Breast Neoplasms*
Loss of PTEN expression is associated with IGFBP2 expression, younger age, and late stage in triple-negative breast cancer

Dean SJ, Perks CM, Holly JM, Bhoo-Pathy N, Looi LM, Mohammed NA, et al.

Am J Clin Pathol, 2014 Mar;141(3):323-33.
PMID: 24515759 DOI: 10.1309/AJCPR11DEAYPTUSL

OBJECTIVES: To investigate the association between PTEN loss and IGFBP2 expression in a series of triple-negative breast cancers and to relate this expression to basal cytokeratin expression and clinicopathologic features.
METHODS: One hundred and one formalin-fixed and paraffin-processed triple-negative breast cancer cases from the University of Malaya Medical Centre were tested immunohistochemically for cytokeratins 5/6 and 14, PTEN, and IGFBP2. The resulting slides were scored for proportion and intensity of staining.
RESULTS: Loss of tumor nuclear and cytoplasmic staining for PTEN occurred in 48.3% of cases and was significantly associated with younger age at diagnosis (47 years compared with 57 years in those without PTEN loss; P = .005). Independent predictors of PTEN loss were late stage at presentation (P = .026), cytokeratin 5/6 positivity (P = .028), and IGFBP2 expression (P = .042). High levels of IGFBP2 expression were seen in 32% of cases; an independent predictor of high levels was cytokeratin 14 negativity (P = .005). PTEN loss and high levels of IGFBP2 expression were associated with poorer survival, but neither of these trends was significant.
CONCLUSIONS: PTEN loss is a frequent event in triple-negative breast cancers and is significantly associated with younger age at onset of breast cancer, late stage, and IGFBP2 expression.

Matched MeSH terms: Triple Negative Breast Neoplasms/metabolism*; Triple Negative Breast Neoplasms/mortality; Triple Negative Breast Neoplasms/pathology
Fulltext Reproductive profiles and risk of breast cancer subtypes: a multi-center case-only study

Brouckaert O, Rudolph A, Laenen A, Keeman R, Bolla MK, Wang Q, et al.

Breast Cancer Res, 2017 Nov 07;19(1):119.
PMID: 29116004 DOI: 10.1186/s13058-017-0909-3

BACKGROUND: Previous studies have shown that reproductive factors are differentially associated with breast cancer (BC) risk by subtypes. The aim of this study was to investigate associations between reproductive factors and BC subtypes, and whether these vary by age at diagnosis.
METHODS: We used pooled data on tumor markers (estrogen and progesterone receptor, human epidermal growth factor receptor-2 (HER2)) and reproductive risk factors (parity, age at first full-time pregnancy (FFTP) and age at menarche) from 28,095 patients with invasive BC from 34 studies participating in the Breast Cancer Association Consortium (BCAC). In a case-only analysis, we used logistic regression to assess associations between reproductive factors and BC subtype compared to luminal A tumors as a reference. The interaction between age and parity in BC subtype risk was also tested, across all ages and, because age was modeled non-linearly, specifically at ages 35, 55 and 75 years.
RESULTS: Parous women were more likely to be diagnosed with triple negative BC (TNBC) than with luminal A BC, irrespective of age (OR for parity = 1.38, 95% CI 1.16-1.65, p = 0.0004; p for interaction with age = 0.076). Parous women were also more likely to be diagnosed with luminal and non-luminal HER2-like BCs and this effect was slightly more pronounced at an early age (p for interaction with age = 0.037 and 0.030, respectively). For instance, women diagnosed at age 35 were 1.48 (CI 1.01-2.16) more likely to have luminal HER2-like BC than luminal A BC, while this association was not significant at age 75 (OR = 0.72, CI 0.45-1.14). While age at menarche was not significantly associated with BC subtype, increasing age at FFTP was non-linearly associated with TNBC relative to luminal A BC. An age at FFTP of 25 versus 20 years lowered the risk for TNBC (OR = 0.78, CI 0.70-0.88, p

Matched MeSH terms: Triple Negative Breast Neoplasms/diagnosis; Triple Negative Breast Neoplasms/etiology; Triple Negative Breast Neoplasms/epidemiology
Fulltext Triple negative breast cancer: the role of metabolic pathways

Dean SJ, Rhodes A

Malays J Pathol, 2014 Dec;36(3):155-62.
PMID: 25500513 MyJurnal

The incidence of breast cancer in Malaysia and other Asian countries is on the increase, reflecting lifestyle changes some of which are known risk factors for the development of breast cancer. Most breast cancers are amenable to adjuvant therapies that target hormone receptors or HER2 receptors on the surface of the cancer cells and bring about significant improvement in survival. However, approximately 17% of Malaysian women with breast cancer, present with tumours that are devoid of these receptors and are consequently termed 'triple negative' breast cancers. These triple negative breast cancers typically occur in women of a younger age than receptor positive cancers, are predominantly of high grade tumours and the prognosis is usually poor. There is therefore a pressing need to understand the biological pathways that drive these tumours, in order that effective strategies are developed to treat these aggressive tumours. With the increasing affluence of developing countries, obesity and Type II Diabetes are also on the rise. These diseases are associated with an increased risk of developing a range of cancers including those of the breast. In particular, the metabolic syndrome has been shown to be associated with triple negative breast cancer. This article reviews some of the metabolic pathways and biomarkers which have been shown to be aberrantly expressed in triple negative breast cancer and highlights some of the ongoing work in this area.

Matched MeSH terms: Triple Negative Breast Neoplasms/metabolism*; Triple Negative Breast Neoplasms/epidemiology
Recent progress in small molecule agents for the targeted therapy of triple-negative breast cancer

Islam R, Lam KW

Eur J Med Chem, 2020 Dec 01;207:112812.
PMID: 32937283 DOI: 10.1016/j.ejmech.2020.112812

Triple-negative breast cancer (TNBC) is the most aggressive type of cancer, with a high risk of death on recurrence. To date, there is a lack of approved targeted agents for the treatment of the disease. Patients with TNBC continue to depend on surgery, chemotherapy, and radiotherapy, all of which have a wide side effect profile. In the present review, we highlight the current progress and exciting developments in the small-molecule targeted therapy for the treatment of TNBC. Finally, we also discuss the prospect of combining targeted therapy and immunotherapy for the effective treatment of TNBC.

Matched MeSH terms: Triple Negative Breast Neoplasms/drug therapy*; Triple Negative Breast Neoplasms/immunology
Metabolic role of fatty acid binding protein 7 in mediating triple-negative breast cancer cell death via PPAR-α signaling

Kwong SC, Jamil AHA, Rhodes A, Taib NA, Chung I

J Lipid Res, 2019 11;60(11):1807-1817.
PMID: 31484694 DOI: 10.1194/jlr.M092379

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, partly due to the lack of targeted therapy available. Cancer cells heavily reprogram their metabolism and acquire metabolic plasticity to satisfy the high-energy demand due to uncontrolled proliferation. Accumulating evidence shows that deregulated lipid metabolism affects cancer cell survival, and therefore we sought to understand the function of fatty acid binding protein 7 (FABP7), which is expressed predominantly in TNBC tissues. As FABP7 was not detected in the TNBC cell lines tested, Hs578T and MDA-MB-231 cells were transduced with lentiviral particles containing either FABP7 open reading frame or red fluorescent protein. During serum starvation, when lipids were significantly reduced, FABP7 decreased the viability of Hs578T, but not of MDA-MB-231, cells. FABP7-overexpressing Hs578T (Hs-FABP7) cells failed to efficiently utilize other available bioenergetic substrates such as glucose to sustain ATP production, which led to S/G2 phase arrest and cell death. We further showed that this metabolic phenotype was mediated by PPAR-α signaling, despite the lack of fatty acids in culture media, as Hs-FABP7 cells attempted to survive. This study provides imperative evidence of metabolic vulnerabilities driven by FABP7 via PPAR-α signaling.

Matched MeSH terms: Triple Negative Breast Neoplasms/metabolism*; Triple Negative Breast Neoplasms/pathology
Fulltext Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Zhang H, Ahearn TU, Lecarpentier J, Barnes D, Beesley J, Qi G, et al.

Nat Genet, 2020 06;52(6):572-581.
PMID: 32424353 DOI: 10.1038/s41588-020-0609-2

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

Matched MeSH terms: Triple Negative Breast Neoplasms/genetics; Triple Negative Breast Neoplasms/pathology
Fulltext Recent advances in nanotheranostics for triple negative breast cancer treatment

Thakur V, Kutty RV

J Exp Clin Cancer Res, 2019 Oct 28;38(1):430.
PMID: 31661003 DOI: 10.1186/s13046-019-1443-1

Triple-negative breast cancer (TNBC) is the most complex and aggressive type of breast cancer encountered world widely in women. Absence of hormonal receptors on breast cancer cells necessitates the chemotherapy as the only treatment regime. High propensity to metastasize and relapse in addition to poor prognosis and survival motivated the oncologist, nano-medical scientist to develop novel and efficient nanotherapies to solve such a big TNBC challenge. Recently, the focus for enhanced availability, targeted cellular uptake with minimal toxicity is achieved by nano-carriers. These smart nano-carriers carrying all the necessary arsenals (drugs, tracking probe, and ligand) designed in such a way that specifically targets the TNBC cells at site. Articulating the targeted delivery system with multifunctional molecules for high specificity, tracking, diagnosis, and treatment emerged as theranostic approach. In this review, in addition to classical treatment modalities, recent advances in nanotheranostics for early and effective diagnostic and treatment is discussed. This review highlighted the recently FDA approved immunotherapy and all the ongoing clinical trials for TNBC, in addition to nanoparticle assisted immunotherapy. Futuristic but realistic advancements in artificial intelligence (AI) and machine learning not only improve early diagnosis but also assist clinicians for their workup in TNBC. The novel concept of Nanoparticles induced endothelial leakiness (NanoEL) as a way of tumor invasion is also discussed in addition to classical EPR effect. This review intends to provide basic insight and understanding of the novel nano-therapeutic modalities in TNBC diagnosis and treatment and to sensitize the readers for continue designing the novel nanomedicine. This is the first time that designing nanoparticles with stoichiometric definable number of antibodies per nanoparticle now represents the next level of precision by design in nanomedicine.

Matched MeSH terms: Triple Negative Breast Neoplasms/pathology; Triple Negative Breast Neoplasms/therapy*
Prognostic role of adjuvant radiotherapy in triple-negative breast cancer: A historical cohort study

Bhoo-Pathy N, Verkooijen HM, Wong FY, Pignol JP, Kwong A, Tan EY, et al.

Int J Cancer, 2015 Nov 15;137(10):2504-12.
PMID: 26018878 DOI: 10.1002/ijc.29617

The value of adjuvant radiotherapy in triple-negative breast cancer (TNBC) is currently debated. We assessed the association between adjuvant radiotherapy and survival in a large cohort of Asian women with TNBC. Women diagnosed with TNBC from 2006 to 2011 in five Asian centers (N = 1,138) were included. Survival between patients receiving mastectomy only, breast-conserving therapy (BCT, lumpectomy and adjuvant radiotherapy) and mastectomy with radiotherapy were compared, and adjusted for demography, tumor characteristics and chemotherapy types. Median age at diagnosis was 53 years (range: 23-96 years). Median tumor size at diagnosis was 2.5 cm and most patients had lymph node-negative disease. The majority of patients received adjuvant chemotherapy (n = 861, 76%) comprising predominantly anthracycline-based regimes. In 775 women with T1-2, N0-1, M0 TNBCs, 5-year relative survival ratio (RSR) was highest in patients undergoing mastectomy only (94.7%, 95% CI: 88.8-98.8%), followed by BCT (90.8%, 95% CI: 85.0-94.7%), and mastectomy with radiotherapy (82.3%, 95% CI: 73.4-88.1%). The adjusted risks of mortality between the three groups were not significantly different. In 363 patients with T3-4, N2-3, M0 TNBCs, BCT was associated with highest 5-year RSR (94.1%, 95% CI: 81.3-99.4%), followed by mastectomy with radiotherapy (62.7%, 95% CI: 54.3-70.1%), and mastectomy only (58.6%, 95% CI: 43.5-71.6%). Following multivariable adjustment, BCT and mastectomy with radiotherapy remained significantly associated with lower mortality risk compared to mastectomy only. Overall, adjuvant radiotherapy was associated with higher survival in women aged <40 years, but not in older women. Adjuvant radiotherapy appears to be independently associated with a survival gain in locally advanced as well as in very young TNBC.

Matched MeSH terms: Triple Negative Breast Neoplasms/drug therapy; Triple Negative Breast Neoplasms/mortality*; Triple Negative Breast Neoplasms/radiotherapy*; Triple Negative Breast Neoplasms/surgery
Single-nucleotide polymorphisms and mRNA expression of CYP1B1 influence treatment response in triple negative breast cancer patients undergoing chemotherapy

Abdul Aziz AA, Md Salleh MS, Mohamad I, Krishna Bhavaraju VM, Mazuwin Yahya M, Zakaria AD, et al.

J Genet, 2018 Dec;97(5):1185-1194.
PMID: 30555068

Triple negative breast cancer (TNBC) is typically associated with poor and interindividual variability in treatment response. Cytochrome P450 family 1 subfamily B1 (CYP1B1) is a metabolizing enzyme, involved in the biotransformation of xenobiotics and anticancer drugs. We hypothesized that, single-nucleotide polymorphisms (SNPs), CYP1B1 142 C>G, 4326 C>G and 4360 A>G, and CYP1B1 mRNA expression might be potential biomarkers for prediction of treatment response in TNBC patients. CYP1B1 SNPs genotyping (76 TNBC patients) was performed using allele-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism methods and mRNA expression of CYP1B1 (41 formalin-fixed paraffin embeddedblocks) was quantified using quantitative reverse transcription PCR. Homozygous variant genotype (GG) and variant allele (G) of CYP1B1 4326C>G polymorphism showed significantly higher risk for development of resistance to chemotherapy with adjusted odds ratio (OR): 6.802 and 3.010, respectively. Whereas, CYP1B1 142 CG heterozygous genotype showed significant association with goodtreatment response with adjusted OR: 0.199. CYP1B1 142C-4326G haplotype was associated with higher risk for chemoresistance with OR: 2.579. Expression analysis revealed that the relative expression of CYP1B1 was downregulated (0.592) in cancerous tissue compared with normal adjacent tissues. When analysed for association with chemotherapy response, CYP1B1 expression was found to be significantly upregulated (3.256) in cancerous tissues of patients who did not respond as opposed to those of patients who showed response to chemotherapy. Our findings suggest that SNPs together with mRNA expression of CYP1B1 may be useful biomarkers to predict chemotherapy response in TNBC patients.

Matched MeSH terms: Triple Negative Breast Neoplasms/drug therapy; Triple Negative Breast Neoplasms/genetics*; Triple Negative Breast Neoplasms/pathology
Tocotrienols Modulate Breast Cancer Secretomes and Affect Cancer-Signaling Pathways in MDA-MB-231 Cells: A Label-Free Quantitative Proteomic Analysis

Ramdas P, Radhakrishnan AK, Abdu Sani AA, Abdul-Rahman PS

Nutr Cancer, 2019;71(8):1263-1271.
PMID: 31084432 DOI: 10.1080/01635581.2019.1607407

Tocotrienols (T3), a family of vitamin E, are reported to possess potent anti-cancer effects but the molecular mechanisms behind these effects still remain unclear. The aim of this study was to investigate how T3 exert anti-cancer effects on MDA-MB-231 human breast cancer cells. The MDA-MB-231 cells were chosen for this study as they are triple-negative and highly metastatic cells, which form aggressive tumors in experimental models. The MDA-MB-231 cells were treated with varying concentrations (0-20 µg mL-1) of gamma (γ) or delta (δ) T3 and the secretome profiles of these cells treated with half maximal inhibitory concentration (IC50) of γT3 (5.8 µg mL-1) or δT3 (4.0 µg mL-1) were determined using label-free quantitative proteomic strategy. A total of 103, 174 and 141 proteins were identified with ProteinLynx Global Server (PLGS) score of more than 200 and above 25% sequence coverage in the untreated control and T3-treated cell culture supernatant respectively. A total of 18 proteins were dysregulated between untreated control and T3 (δT3 or γT3) treated conditions. The results showed that T3 treatment downregulated the exogenous Cathepsin D and Serpine1 proteins but upregulated Profilin-1 protein, which play a key role in breast cancer in the MDA-MB-231 cells. These findings strongly suggest that T3 may induce differential expression of secreted proteins involved in the cytoskeletal regulation of RHO GTPase signaling pathway.

Matched MeSH terms: Triple Negative Breast Neoplasms/drug therapy; Triple Negative Breast Neoplasms/metabolism*; Triple Negative Breast Neoplasms/pathology
Fulltext Genetic Association of CYP1B1 4326 C>G Polymorphism with Disease-Free Survival in TNBC Patients Undergoing TAC Chemotherapy Regimen

Abdul Aziz AA, Md Salleh MS, Yahya MM, Zakaria AD, Ankathil R

Asian Pac J Cancer Prev, 2021 Apr 01;22(4):1319-1324.
PMID: 33906328 DOI: 10.31557/APJCP.2021.22.4.1319

BACKGROUND: Triple negative breast cancer (TNBC) which is treated with taxane, adriamycin and cyclophosphamide (TAC) chemotherapy regimen show variation in treatment response. CYP1B1 4326 C>G polymorphism has been implicated in contributing to the differences in treatment response in various types of cancers.
AIM: The objective of the present study was to investigate whether this polymorphism modulate the risk of disease recurrence in TNBC patients undergoing TAC chemotherapy regimen.
METHODS: Blood samples of 76 immunohistochemistry confirmed TNBC patients were recruited. The genotyping of CYP1B1 4326 C>G polymorphism was carried out using PCR-RFLP technique. The genotype patterns were categorized into homozygous wildtype, heterozygous and homozygous variant. Kaplan-Meier analysis followed by Cox proportional hazard regression model were performed to evaluate the TNBC patients' recurrence risk.
RESULTS: Out of 76 TNBC patients, 25 (33.0%) showed disease recurrence after one-year evaluation. Kaplan Meier analysis showed that TNBC patients who are carriers of CYP1B1 4326 GG variant genotypes (37.0%) had a significantly lower probability of disease-free rates as compared to TNBC patients who are carriers of CYP1B1 4326 CC/CG genotypes (71.0%). Univariate and multivariate Cox analysis demonstrated that TNBC patients who carried CYP1B1 4326 GG variant genotype had a significantly higher risk of recurrence with HR: 2.50 and HR: 4.18 respectively, even after adjustment as compared to TNBC patients who were carriers of CYP1B1 4326 CC and CG genotypes.
CONCLUSION: Our results demonstrate the potential use of CYP1B1 4325 GG variant genotype as a candidate biomarker in predicting risk of recurrence in TNBC patients undergoing TAC chemotherapy regimen.

Matched MeSH terms: Triple Negative Breast Neoplasms/drug therapy; Triple Negative Breast Neoplasms/genetics*; Triple Negative Breast Neoplasms/mortality*
Overview on Epigenetic Re-programming: A Potential Therapeutic Intervention in Triple Negative Breast Cancers

Mohamad Hanif EA, Shah SA

Asian Pac J Cancer Prev, 2018 Dec 25;19(12):3341-3351.
PMID: 30583339

Breast cancer treatments leads to variable responses. Hormonal therapy is beneficial to receptor positive breast cancer
subtypes and display better clinical outcome than triple negative breast cancers (TNBCs) with FEC (5-Fluorouracil,
Epirubicin and Cyclophosphamide) the mainstay chemotherapy regiment. Owning to their negative expressions of
estrogen (ER), progesterone (PR) and HER2 receptors, disease recurrence and metastasis befalls some patients indicating
resistance to FEC. Involvement of epigenetic silencing through DNA methylation, histone methylation, acetylation and
sumoylation may be the key player in FEC chemoresistance. Epigenetic and molecular profiling successfully classified
breast cancer subtypes, indicating potential driver mechanisms to the progression of TNBCs but functional mechanisms
behind chemoresistance of these molecular markers are not well defined. Several epigenetic inhibitors and drugs have
been used in the management of cancers but these attempts are mainly beneficial in hematopoietic cancers and not
specifically favourable in solid tumours. Hypothetically, upon administration of epigenetic drugs, recovery of tumour
suppressor genes is expected. However, high tendency of switching on global metastatic genes is predicted. Polycomb
repressive complex (PRC) such as EZH2, SETD1A, DNMT, is known to have repressive effects in gene regulation and
shown to inhibit cell proliferation and invasion in breast cancers. Individual epigenetic regulators may be an option
to improve chemo-drug delivery in cancers. This review discussed on molecular signatures of various breast cancer
subtypes and on-going attempts in understanding underlying molecular mechanisms of epigenetic regulators as well
as providing insights on possible ways to utilize epigenetic enzymes/inhibitors with responses to chemotherapeutic
drugs to re-program cellular and biological outcome in TNBCs.

Matched MeSH terms: Triple Negative Breast Neoplasms/genetics*
Dysregulation of non-histone molecule miR205 and LRG1 post-transcriptional de-regulation by SETD1A in triple negative breast cancer

Mohamad Hanif EA

Mol Biol Rep, 2019 Dec;46(6):6617-6624.
PMID: 31552595 DOI: 10.1007/s11033-019-05079-w

FEC chemo-resistance in triple negative breast cancer (TNBC) remains a challenge. Therefore it is crucial to determine the right treatment regime by understanding molecular mechanisms of driver regulators involved in the progression of TNBCs. This study aims to understand SETD1A mechanisms in TNBC development in two TNBC cell lines. SETD1A was transiently transfected in MDA-MB-468 (FEC good prognosis) and Hs578T (FEC poor prognosis). Regulation of potential targets miR205, EMT marker ZEB1 and LRG1 and proliferative marker Ki-67 were tested by RqPCR to elucidate SETD1A interactions. This study displayed significant recovery of miR205 with SETD1A depletion and reduction of ZEB1 in MDA-MB-468. However, ZEB1 remained unchanged in Hs578T indicating ZEB1 regulation may be outcompeted by other mechanisms associated with aggressive cell line characteristics and the expression of endogenous ZEB1 was relatively high in Hs578T. Elevation of LRG1 and declined Ki-67 were observed by SETD1A knocked down. Enhanced expression was observed by LRG1 in Hs578T and not in MDA-MB-468 suggesting LRG1 contributed to distinct poor FEC outcome in TNBCs. The underlying mechanism of SETD1A in miR205/ZEB1/Ki-67/LRG1 axis needs further evaluation. Whether abrogation of the pathway is indeed associated with transcriptional or post-transcriptional activation in TNBC cell lines models, clearly validation in clinical samples is warranted to achieve its prognostic and therapeutic values in TNBCs.

Matched MeSH terms: Triple Negative Breast Neoplasms/genetics*
Bioactive chemical constituents from Curcuma caesia Roxb. rhizomes and inhibitory effect of curcuzederone on the migration of triple-negative breast cancer cell line MDA-MB-231

Al-Amin M, Eltayeb NM, Khairuddean M, Salhimi SM

Nat Prod Res, 2021 Sep;35(18):3166-3170.
PMID: 31726856 DOI: 10.1080/14786419.2019.1690489

Rhizomes of Curcuma caesia are traditionally used to treat cancer in India. The aim is to isolate chemical constituents from C. caesia rhizomes through bioassay-guided fractionation. The extract, hexanes and chloroform fractions showed effect on MCF-7 and MDA-MB-231cells in cell viability assay. The chromatographic separation afforded germacrone (1), zerumbone (2), furanodienone (3), curzerenone (4), curcumenol (5), zederone (6), curcumenone (7), dehydrocurdione (8) from hexanes fraction and curcuminol G (9), curcuzederone (10), (1S, 10S), (4S,5S)-germacrone-1 (10), 4-diepoxide (11), wenyujinin B (12), alismoxide (13), aerugidiol (14), zedoarolide B (15), zedoalactone B (16), zedoarondiol (17), isozedoarondiol (18) from chloroform fraction. This is first report of compounds 2, 9-13, 15-18 from C. caesia. The study demonstrated compounds 1-4 and 10 are the bioactive compounds. The effect of curcuzederone (10) on MDA-MB-231 cell migration showed significant inhibition in scratch and Transwell migration assays. The results revealed that curcuzederone could be a promising drug to treat cancer.

Matched MeSH terms: Triple Negative Breast Neoplasms*
Green synthesis of chitosan/silver nanocomposite using kaempferol for triple negative breast cancer therapy and antibacterial activity

Bharathi D, Ranjithkumar R, Nandagopal JGT, Djearamane S, Lee J, Wong LS

Environ Res, 2023 Dec 01;238(Pt 1):117109.
PMID: 37696324 DOI: 10.1016/j.envres.2023.117109

The synthesis of polymer-encapsulated metal nanoparticles is a growing field of area due to their long-term uses in the development of new technologies. The present study describes the synthesis of chitosan/silver nanocomposite using kaempferol for anticancer and bactericidal activity. The formation of Kf-CS/Ag nanocomposite was confirmed by the development of a brown color and UV-absorbance around 438 nm. The IR study was utilized to determine the existence of Kf and CS in the synthesized nanocomposite. TEM analysis demonstrated that the synthesized nanocomposite have a predominantly uniform spherical shape and size ranges 7-10 nm. EDX spectrum showed the existence of Ag, C, and N elements in the nanocomposite material. Further, Kf-CS/Ag nanocomposite exhibited potential in vitro inhibitory property against triple-negative breast cancer (TNBC) cells and their IC50 values was found to be 53 μg/mL. Moreover, fluorescent assays such as DAPI and AO/EtBr confirmed the apoptosis induction ability of Kf-CS/Ag nanocomposite in MDA-MB-231 cells. The synthesized Kf-CS/Ag nanocomposite showed significant and dose-depended antibacterial property against S. aureus and P. aeruginosa. Thus, the obtained findings demonstrated that the synthesized nanocomposite can be potentially used to improve human health as biocidal nanocomposite in biomedical sectors.

Matched MeSH terms: Triple Negative Breast Neoplasms*

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