Displaying publications 1 - 20 of 41 in total

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  1. 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
  2. Yip CH, Bhoo Pathy N, Teo SH
    Med J Malaysia, 2014 Aug;69 Suppl A:8-22.
    PMID: 25417947 MyJurnal
    Four hundred and nineteen articles related to breast cancer were found in a search through a database dedicated to indexing all original data relevant to medicine published in Malaysia between the years 2000-2013. One hundred and fifty four articles were selected and reviewed on the basis of clinical relevance and future research implications. Overall, Malaysian women have poor survival from breast cancer and it is estimated that half of the deaths due to breast cancer could be prevented. Five-year survival in Malaysia was low and varies among different institutions even within the same disease stage, suggesting an inequity of access to optimal treatment or a lack of compliance to optimal treatment. Malaysian women have poor knowledge of the risk factors, symptoms and methods for early detection of breast cancer, leading to late presentation. Moreover, Malaysian women experience cancer fatalism, belief in alternative medicine, and lack of autonomy in decision making resulting in delays in seeking or avoidance of evidence-based medicine. There are ethnic differences in estrogen receptor status, HER2 overexpression and incidence of triple negative breast cancer which warrant further investigation. Malay women present with larger tumours and at later stages, and even after adjustment for these and other prognostic factors (stage, pathology and treatment), Malay women have a poorer survival. Although the factors responsible for these ethnic differences have not been elucidated, it is thought that pharmacogenomics, lifestyle factors (such as weight-gain, diet and exercise), and psychosocial factors (such as acceptance of 2nd or 3rd line chemotherapy) may be responsible for the difference in survival. Notably, survivorship studies show self-management programmes and exercise improve quality of life, highlighting the need to evaluate the psychosocial impact of breast cancer on Malaysian women, and to design culturally-, religiously- and linguistically-appropriate psycho-education programmes to help women cope with the disease and improve their quality of life. Research done in the Caucasian populations may not necessarily apply to local settings and it is important to embark on local studies particularly prevention, screening, diagnostic, prognostic, therapeutic and psychosocial research.
    Matched MeSH terms: Triple Negative Breast Neoplasms
  3. 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
  4. Ayub A, Yip WK, Seow HF
    Biomed Pharmacother, 2015 Oct;75:40-50.
    PMID: 26463630 DOI: 10.1016/j.biopha.2015.08.031
    Triple-negative breast cancers (TNBCs) are aggressive cancers that do not benefit from hormonal therapy or therapies that target HER2 receptors. Insulin-like growth factor 1 receptor (IGF-1R), which has been shown to be overexpressed in breast cancer, activates numerous downstream kinases that associate with cell proliferation and survival. This study compared the effects caused by dual treatments targeting IGF-1R, PI3K, mTORC, or MEK with those by single treatments in a TNBC cell line, MDA-MB-231. We used small-molecule kinase inhibitors, namely, NVP-AEW541, NVP-BKM120, KU0063794, and PD0325901 to target IGF-1R, PI3K, mTORC, and MEK, respectively. Combination treatments of PD0325901 with NVP-AEW541, NVP-BKM120 or KU0063794 and NVP-AEW541 with KU0063794 demonstrated a significant synergistic growth inhibition. These dual treatments increased apoptosis and/or cell cycle arrest at G0/G1 phase and enhanced the inhibition of phosphorylation of Akt or downstream molecules of mTORC1, as compared to the single treatments. Our study suggests that targeting multiple kinases in IGF-1R signaling may be a promising therapeutic approach.
    Matched MeSH terms: Triple Negative Breast Neoplasms
  5. 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
  6. Nakagawa-Goto K, Chen JY, Cheng YT, Lee WL, Takeya M, Saito Y, et al.
    Mol Oncol, 2016 06;10(6):921-37.
    PMID: 27055598 DOI: 10.1016/j.molonc.2016.03.002
    Triple-negative breast cancer (TNBC) is associated with high grade, metastatic phenotype, younger patient age, and poor prognosis. The discovery of an effective anti-TNBC agent has been a challenge in oncology. In this study, fifty-eight ester derivatives (DETDs) with a novel sesquiterpene dilactone skeleton were organically synthesized from a bioactive natural product deoxyelephantopin (DET). Among them, DETD-35 showed potent antiproliferative activities against a panel of breast cancer cell lines including TNBC cell line MDA-MB-231, without inhibiting normal mammary cells M10. DETD-35 exhibited a better effect than parental DET on inhibiting migration, invasion, and motility of MDA-MB-231 cells in a concentration-dependent manner. Comparative study of DETD-35, DET and chemotherapeutic drug paclitaxel (PTX) showed that PTX mainly caused a typical time-dependent G2/M cell-cycle arrest, while DETD-35 or DET treatment induced cell apoptosis. In vivo efficacy of DETD-35 was evaluated using a lung metastatic MDA-MB-231 xenograft mouse model. DETD-35 significantly suppressed metastatic pulmonary foci information along with the expression level of VEGF and COX-2 in SCID mice. DETD-35 also showed a synergistic antitumor effect with PTX in vitro and in vivo. This study suggests that the novel compound DETD-35 may have a potential to be further developed into a therapeutic or adjuvant agent for chemotherapy against metastatic TNBC.
    Matched MeSH terms: Triple Negative Breast Neoplasms/drug therapy*; Triple Negative Breast Neoplasms/pathology
  7. Alcantara VS, Lim GH, Lim SH, Sultana R, Lee JA
    J Surg Oncol, 2017 Apr;115(5):523-537.
    PMID: 28168712 DOI: 10.1002/jso.24559
    BACKGROUND AND OBJECTIVES: Triple negative breast cancer (TNBC) carries a worse prognosis compared to the other subtypes. There have been conflicting studies that race may impact the prognosis of TNBC patients. We aim to determine the incidence and prognosis of TNBC among the different ethnic races in Singapore, and to determine its associated risk factors for prognosis.

    METHODS: Patients diagnosed with invasive breast cancer (BC) from 2005 to 2013 at our tertiary institution were included and divided according to race and subtypes. Demographic and clinical information of non-metastatic TNBC patients were analyzed. Log-rank test, univariate and multivariate Cox proportional hazard regression models were used to find associated risk factors related with overall survival (OS) and disease-free survival (DFS).

    RESULTS: Among 1227 BC patients, 129 (10.5%) had TNBC. TNBC patients had the worst OS (P: 0.0005) and DFS (P: 0.0016) among the subtypes. However, variations in race did not have any difference in OS or DFS among TNBC patients. Axillary lymph node involvement, invasive lobular histology, larger tumor size, and the presence of lymphovascular invasion (LVI) were factors associated with both poor DFS and OS among TNBC patients.

    CONCLUSIONS: Racial variation did not have any impact on the prognosis of the TNBC.

    Matched MeSH terms: Triple Negative Breast Neoplasms/mortality*; Triple Negative Breast Neoplasms/pathology; Triple Negative Breast Neoplasms/therapy
  8. 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*
  9. 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
  10. Engku Fatimah Syairah Engku Safruddin, Wan Zainira Wan Zain, Bhavaraju, Venkata Murali Krishna, Kannan, Thirumulu Ponnuraj
    MyJurnal
    Given that the germline mutations of BRCA1 and BRCA2 confer genetic susceptibility to cancer, the
    genetic variations, polymorphisms or mutations are widely analyzed in Western countries. However, in Asian
    population, the prevalence of BRCA1 and BRCA2 polymorphisms is very limited. In Asia, breast cancer occurs in
    women early with an age of onset under 50 years. This review comprises the incidence of BRCA1 and BRCA2
    polymorphisms in the Japanese, Korean and Malaysian population. Founder mutations of BRCA1 and BRCA2
    were also compared to mark the genetic difference in these populations. The mutational analysis performed to
    analyze the entire coding region of BRCA1 and BRCA2 include the next generation sequencing and full
    sequencing of all exons and intron-exon junctions. From the diagnosis of triple negative breast cancer (TNBC)
    patients, TNBC is associated with the lack of tailored therapies and the treatment option available for TNBC
    patients is mainly chemotherapy. The poor prognosis of TNBC leads to determine the predictive biomarkers in
    order to develop treatment efficacy. This review will address the current clinical therapies available to treat TNBC
    patients.
    Matched MeSH terms: Triple Negative Breast Neoplasms
  11. Etti IC, Abdullah R, Kadir A, Hashim NM, Yeap SK, Imam MU, et al.
    PLoS One, 2017;12(8):e0182357.
    PMID: 28771532 DOI: 10.1371/journal.pone.0182357
    Nature has provided us with a wide spectrum of disease healing phytochemicals like Artonin E, obtained from the root bark of Artocarpus elasticus. This molecule had been predicted to be drug-like, possessing unique medicinal properties. Despite strides made in chemotherapy, prognosis of the heterogenous aggressive triple negative breast cancer is still poor. This study was conducted to investigate the mechanism of inhibition of Artonin E, a prenylated flavonoid on MDA-MB 231 triple negative breast cancer cell, with a view of mitigating the hallmarks displayed by these tumors. The anti-proliferative effect, mode of cell death and the mechanism of apoptosis induction were investigated. Artonin E, was seen to effectively relinquish MDA-MB 231 breast cancer cells of their apoptosis evading capacity, causing a half-maximal growth inhibition at low concentrations (14.3, 13.9 and 9.8 μM) after the tested time points (24, 48 and 72 hours), respectively. The mode of cell death was observed to be apoptosis with defined characteristics. Artonin E was seen to induce the activation of both extrinsic and intrinsic caspases initiators of apoptosis. It also enhanced the release of total reactive oxygen species which polarized the mitochondrial membrane, compounding the release of cytochrome c. Gene expression studies revealed the upregulation of TNF-related apoptosis inducing ligand and proapoptotic genes with down regulation of anti-apoptotic genes and proteins. A G2/M cell cycle arrest was also observed and was attributed to the observed upregulation of p21 independent of the p53 status. Interestingly, livin, a new member of the inhibitors of apoptosis was confirmed to be significantly repressed. In all, Artonin E showed the potential as a promising candidate to combat the aggressive triple negative breast cancer.
    Matched MeSH terms: Triple Negative Breast Neoplasms/metabolism; Triple Negative Breast Neoplasms/pathology
  12. Khurana RK, Kumar R, Gaspar BL, Welsby G, Welsby P, Kesharwani P, et al.
    Mater Sci Eng C Mater Biol Appl, 2018 Oct 01;91:645-658.
    PMID: 30033299 DOI: 10.1016/j.msec.2018.05.010
    The current studies envisage unravelling the underlying cellular internalisation mechanism of the systematically developed docetaxel (DTH) polyunsaturated fatty acid (PUFA) enriched self-nanoemulsifying lipidic micellar systems (SNELS). The concentration-, time- and cytotoxicity-related effects of DTH-SNELS on triple negative breast cancer (TNBC) MDA-MB-231 and non-TNBC MCF-7 cell lines were assessed through Presto-blue assay. Subsequently, rhodamine-123 (Rh-123) loaded SNELS were employed for evaluating their internalisation through flow cytometry and fluorescence microscopy, establishing it to be "clathrin-mediated" endocytic pathway. Apoptosis assay (65% cell death) and cell cycle distribution (47% inhibition at G2/M phase) further corroborated the cytotoxicity of DTH-SNELS towards cancerous cells. Biodistribution, histopathology and haematology studies indicated insignificant toxicity of the optimized formulation on vital organs. Preclinical anticancer efficacy studies using 7,12-dimethylbenzantracene (DMBA)-induced model construed significant reduction in breast tumor-volume. Overall, extensive in vitro and in vivo studies indicated the intracellular localization and cytotoxicity, suggesting DTH-SNELS as promising delivery systems for breast tumor therapeutics including TNBC.
    Matched MeSH terms: Triple Negative Breast Neoplasms
  13. 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
  14. 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*
  15. Hasanpourghadi M, Abdul Majid N, Rais Mustafa M
    PeerJ, 2018;6:e5577.
    PMID: 30245930 DOI: 10.7717/peerj.5577
    Combination Index (CI) analysis suggested that MBIC and doxorubicin synergistically inhibited up to 97% of cell proliferation in ER+/PR+MCF-7 and triple negative MDA-MB-231 breast cancer cell lines. Moreover, treatment of the breast cancer cells with the combined drugs resulted in lower IC50 values in contrast to the individual drug treatment. Small noncoding microRNAs (miRNA) may function as non-mutational gene regulators at post-transcriptional level of protein synthesis. In the present study, the effect of the combined treatment of MBIC and doxorubicin on the expression level of several miRNAs including miR-34a, miR-146a, miR-320a and miR-542 were evaluated in MCF-7 and MDA-MB-231 breast cancer cell lines. These miRNAs have the potential to alter the protein level of survivin, the anti-apoptotic protein and reduce the metastatic activity in human breast cancer cell lines by interfering with the nuclear accumulation of NF-κB. Our results demonstrated the several fold changes in expression of miRNAs, which is drug and cell line dependent. This finding demonstrated a functional synergistic network between miR-34a, miR-320a and miR-542 that are negatively involved in post-transcriptional regulation of survivin in MCF-7 cells. While in MDA-MB-231 cells, changes in expression level of miR-146a was correlated with inhibition of the nuclear translocation of NF-κB. The overall result suggested that alteration in protein level and location of survivin and NF-κB by miR-34a, miR-320a, miR-146a and miR-542, remarkably influenced the synergistic enhancement of combined MBIC and doxorubicin in treatment of aggressive and less aggressive human breast cancer cell lines.
    Matched MeSH terms: Triple Negative Breast Neoplasms
  16. Venugopal V, Krishnan S, Palanimuthu VR, Sankarankutty S, Kalaimani JK, Karupiah S, et al.
    PLoS One, 2018;13(11):e0206109.
    PMID: 30408068 DOI: 10.1371/journal.pone.0206109
    The aim of the present study is to analyze the viability of anti-EGFR anchored immunonanoparticle (INP) bearing Paclitaxel (PTX) to specifically bind the EGFR protein on the TNBC cells. The NP was prepared by nanoprecipitation and characterized the particle size, charge, entrapment of drug and release of it. The anti-EGFR anchored and the integrity was confirmed by SDS-PAGE. Cytotoxicity and NPs cellular uptake was analyzed with MDA-MB-468 type cancer cells and the EGFR expression was confirmed by PCR, qualitatively and quantitatively. The in-vivo antitumor activity of INP was determined by using athymic mice model and targeting efficiency was measured by calculating the PTX accumulation in the tumor plasma. The prepared INP with the size of 336.3 nm and the charge of -3.48 mV showed sustained drug release upto 48 h. The INP showed significant reduction of cancer cell viability of 10.6% for 48 h with 93 fold higher PTX accumulation in the tumor plasma compared with NPs. Based on these reports, we recommend that anti-EGFR anchored PTX loaded NP may have the ability to target the TNBC cells and improve the therapeutic action and subsidize the side effects of PTX for the treatment of TNBC.
    Matched MeSH terms: Triple Negative Breast Neoplasms/drug therapy*; Triple Negative Breast Neoplasms/pathology
  17. Tieng FYF, Latifah SY, Md Hashim NF, Khaza'ai H, Ahmat N, Gopalsamy B, et al.
    Molecules, 2019 Jul 18;24(14).
    PMID: 31323836 DOI: 10.3390/molecules24142619
    Breast cancer is the most common and the second leading cause of cancer-related deaths in women. It has two distinctive hallmarks: rapid abnormal growth and the ability to invade and metastasize. During metastasis, cancer cells are thought to form actin-rich protrusions, called invadopodia, which degrade the extracellular matrix. Current breast cancer treatments, particularly chemotherapy, comes with adverse effects like immunosuppression, resistance development and secondary tumour formation. Hence, naturally-occurring molecules claimed to be less toxic are being studied as new drug candidates. Ampelopsin E, a natural oligostilbene extracted from Dryobalanops species, has exhibited various pharmacological properties, including anticancer and anti-inflammatory activities. However, there is yet no scientific evidence of the effects of ampelopsin E towards metastasis. Scratch assay, transwell migration and invasion assays, invadopodia and gelatin degradation assays, and ELISA were used to determine the effects of ampelopsin E towards the invasiveness of MDA-MB-231 cells. Strikingly in this study, ampelopsin E was able to halt migration, transmigration and invasion in MDA-MB-231 cells by reducing formation of invadopodia and its degradation capability through significant reduction (p < 0.05) in expression levels of PDGF, MMP2, MMP9 and MMP14. In conclusion, ampelopsin E reduced the invasiveness of MDA-MB-231 cells and was proven to be a potential alternative in treating TNBC.
    Matched MeSH terms: Triple Negative Breast Neoplasms
  18. Teoh PY, Tan GC, Mahsin H, Wong YP
    Malays J Pathol, 2019 Aug;41(2):125-132.
    PMID: 31427547
    INTRODUCTION: Androgen receptor (AR) is the most frequently expressed biomarker in all subtypes of breast carcinoma. Triple negative breast carcinoma (TNBC) is breast carcinoma that lacks oestrogen and progesterone receptors immunoexpression as well as absence of HER2/neu gene amplification. This makes targeted therapy not feasible in this cancer and hence has poorer prognosis. Detecting AR expression could be another milestone in the management of TNBC, as AR is a prognostic, predictive marker and potential index for targeted treatment. This study aimed to assess expression of AR in TNBC by immunohistochemistry and its association with clinicopathological parameters.

    METHODS: We analysed the expression of AR in 97 TNBC cases from Penang General Hospital for a period of 3 years (2014 to 2017). Androgen receptor immunoreactivity was considered positive if ≥ 1% of tumour cells nuclei were stained irrespective of staining intensity.

    RESULTS: The prevalence of AR expression in TNBC was 31% (30/97), with the proportion of AR-positive tumour cells ranged from 1% to 90%. These include 23 invasive carcinomas, no special type (NST) and 7 other invasive carcinoma subtypes (papillary, lobular, clear cell and medullary carcinomas). Sixty-seven cases (69%) that showed AR immunonegativity were invasive carcinomas, NST (n=60), clear cell carcinoma (n=1) and metaplastic carcinoma (n=6). Androgen receptor immunoexpression was inversely correlated with tumour grade (p=0.016), but not the tumour stage, tumour size and nodal status.

    CONCLUSION: AR is expressed in about one-third of TNBC and loss of AR immunoexpression does not predict adverse clinical outcomes. Larger cohorts for better characterisation of the role of AR immunoexpression in TNBC are warranted.

    Matched MeSH terms: Triple Negative Breast Neoplasms
  19. 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*
  20. 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
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