Top PDF Multi-targeted kinase inhibition alleviates mTOR inhibitor resistance in triple-negative breast cancer

Multi-targeted kinase inhibition alleviates mTOR inhibitor resistance in triple-negative breast cancer

Multi-targeted kinase inhibition alleviates mTOR inhibitor resistance in triple-negative breast cancer

activity, allowing well-informed prediction of structure- based alternative kinase target prediction [ 33 , 34 ]. We firstly performed ligand-based target prediction for AEE788. With 1 µM and 10 µM activity cutoffs, 9 kinases showed high prediction scores and as such putative targets of AEE788, including RPS6KB1, AKT2, CDK7, EGFR, MAPKAPK2, CLK4, JAK2, AKT3, and VEGFR2 (Fig.  5 a). To refine the scale of target list, we selected kinases showing prediction score greater than 0.1 and kinases with an IC50 of AEE788 smaller than 1 µM according to the publically available data [ 35 ]. As a result, 30 putative kinase targets were selected. To validate the potential contribution of these kinases in the interaction with rapamycin, we performed a targeted rapa- mycin and siRNA synthetic lethal screen in SUM149PT cells (Fig.  5 b). The synthetic lethal screen revealed 13 can- didate targets (Fig.  5 c). We anticipated that these validated targets would take part in connected signaling networks and, therefore, would all individually impact on the rapamycin sensitivity. Indeed, protein–protein interaction network analysis revealed a close interaction of the various putative kinase targets of AEE788 (Fig.  5 d; Suppl. Table S2). Inter- estingly, the well-known mTOR target RPS6KB1 as well as other RPS6K family members RPS6KA3, RPS6KA6, and RPS6KL1 were mapped in the network, supporting the synergistic drug interaction of AEE788 with rapamy- cin on mTOR signaling. In addition, ABL2 and PDGFRB were predicted and validated as potential targets involved in rapamycin synergy. Of relevance, rapalog-resistant TNBC cell lines SUM149PT, HCC1143, SUM159PT, and HCC38 poorly responded to inhibitors targeting the verified targets of AEE788, including EGFR, VEGFR, PDGFR, ABL, and S6K (Suppl. Fig. S2). Taken together, the above data sug- gest that AEE788 synergizes with rapamycin in suppress- ing TNBC cell proliferation by targeting several EGFR, VEGFR, PDGFR, ABL, and different S6K kinases that are all connected to mTOR signaling.
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A kinase inhibitor screen identifies a dual cdc7/CDK9 inhibitor to sensitise triple negative breast cancer to EGFR targeted therapy

A kinase inhibitor screen identifies a dual cdc7/CDK9 inhibitor to sensitise triple negative breast cancer to EGFR targeted therapy

sensitivity to EGFR-TKIs (Fig. 1d). Next, three TNBC cell lines highly resistant to EGFR-TKIs, Hs578T, BT549 and SKBR7, and one sensitive cell line, HCC1806, were selected for further evaluation. Hs578T, BT549 and SKBR7 cells were resistant to lapatinib-mediated growth inhibition up to and including concentrations of 3.16 μM, but superior concen- trations (10 μM) impeded cellular proliferation (Fig. 1e). Concordantly, lapatinib failed to significantly induce apop- tosis in these cell lines at 3.16 μM (Additional file 3: Figure S1a). In contrast, HCC1806 cells displayed enhanced growth inhibition in response to lapatinib (IC50 ~ 100 nM; Fig. 1e) with significantly increased Annexin-V apoptotic signal (Additional file 3: Figure S1a). Regardless of their response to lapatinib, all these cell lines maintained functional EGFR- mediated signal transduction, with prominent phosphoryl- ation of EGFR (Y1173) and downstream components AKT (S473) and ERK1/2 (T202/Y204) in response to EGF stimu- lation (Fig. 1f ), indicating that resistance was not due to the absence of a functionally intact EGFR pathway. In re- sponse to lapatinib, EGFR phosphorylation was com- pletely inhibited in all cell lines (Fig. 1f ). However, EGF- induced ERK activation persisted in all lapatinib-resistant cell lines, with AKT phosphorylation also unaffected in Hs578T and BT549 cells. These data suggest that these re- sistant cells are capable of bypassing EGFR kinase inhib- ition through the activation of downstream pro- proliferative pathways. Despite the lack of impact of EGFR-TKIs on TNBC proliferation, siRNA-mediated si- lencing of EGFR and downstream components, including ERK2 and FRAP1 (mTOR), led to a significant reduction in cell proliferation, supporting the notion that TNBC cells depend to a certain extent on EGFR-mediated signal- ling for their proliferation (Additional file 3: Figure S1b).
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Novel targeted agents in Her-2 positive and triple negative breast cancer

Novel targeted agents in Her-2 positive and triple negative breast cancer

also identified among others EphA2 and Src as targets of dasatinib in triple negative breast cancer (95) (33) (30) (105). However, all triple negative cell lines tested were resistant to PP2, a laboratory grade selective Src inhibitor. These results suggest that targeting EphA receptors contributes to sensitivity to dasatinib in triple negative breast cancer cells. Consistent with this hypothesis, protein expression analysis in the panel of cell lines showed that dasatinib- sensitive cell lines had higher levels of expression of EphA2 compared to dasatinib-resistant cell lines. EphA2 receptor overexpression has been detected in a variety of cancers, including the majority of breast cancers (106) (107). In addition, higher levels of EphA2 protein have been detected in triple negative breast cancer cell lines as opposed to nontransformed epithelial cells. Upregulation of Eph receptor signalling has been implicated in tumour growth, invasion, resistance to anoikis and neovascularisation (108). In addition,we found elevated caveolin-1 and -2 levels in the dasatinib-sensitive cells. Caveolins interact closely with the Src family kinase and have been identified as markers of basal breast cancer (109) (110).
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Triple negative breast cancer: Shedding light onto the role of pi3k/akt/mtor pathway

Triple negative breast cancer: Shedding light onto the role of pi3k/akt/mtor pathway

Since the PI3K/AKT pathway stabilizes the function of HR, Ibrahim and collaborators have demonstrated that the use of AKT inhibitors in TNBC cell lines without BRCA1/2 alterations could cause HR function changes, and then sensitize to PARPis. In particular, the study showed that TNBC cancer cells treated with buparlisib (AKT inhibitor) were subject to a subsequent hyperactivation of ERK and MEK1, two essential component of the MAP kinase signal transduction pathway, resulting in downregulation of BRCA1 and then favoring the action of olaparib (PARPi) with subsequent reduction of cell proliferation and survival [103]. An interesting in vitro study showed that targeting multiple kinases such as IGF-1R, PI3K, mTORC or MEK may suppress cell proliferation and induce apoptosis in MDA- MB-231 cells, increasing also the inhibition of Akt phosphorylation [104].
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AMP activated protein kinase: a potential therapeutic target for triple negative breast cancer

AMP activated protein kinase: a potential therapeutic target for triple negative breast cancer

We can presume that AMPK activation may counteract the development of cancer through reprogramming cel- lular metabolism and targeting one of the essential com- ponents necessary for tumor progression. In fact, AMPK function is compromised in primary BCs and loss of AMPK signaling is related to a worse clinical outcome, implicating that AMPK reactivation has the potential for prevention and treatment in BC. Recently, the possible role of an abnormal AMPK signaling pathway in the growth, survival, and drug resistance of TNBC has been well understood. Of pertinence to this review, various AMPK agonists such as metformin, AICAR, RL71, DMC, Fluoxetine, miR-200a, and OSU-53 were demon- strated to significantly inhibit TNBC. Activation of AMPK has positive effects in TNBCs because of its tar- geting inhibition effect on Akt/mTOR. Additionally, AMPK activation suppresses EGFR, c-Myc, IL6, Jak/ STAT3, HIF-1α, and eEF2K, which are well-established hallmarks of TNBCs. On the other hand, under certain circumstances, such as in combination with DNA dam- aging therapeutic agents or glycolytic inhibitors, inhib- ition of AMPK can also be used as a means to treat TNBC. Therefore, it is plausible to consider AMPK as an attractive therapeutic target for TNBC (Fig. 2).
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Molecular Classification of Triple-Negative Breast Cancer

Molecular Classification of Triple-Negative Breast Cancer

In 2011, the researchers of the Vanderbilt University report- ed a seminal study classifying TNBC into distinct subtypes [8]. Using gene expression analyses from 587 TNBC tumors, they illustrated that TNBC consists of six distinguished subtypes and displays a unique biology that responds differently to vari- ous therapies. By k-means and consensus clustering, they found the following six subtypes: two basal-like subtypes, one with increased cell cycle and DNA damage response gene sig- natures (BL1) and the other one with high expression growth factor pathway and myoepithelial markers (BL2); two mesen- chymal subtypes with up-regulated gene signatures associated with cell differentiation and growth factor signaling (M and MSL); an immunomodulatory (IM) type with enriched im- mune cell processes; and a luminal androgen subtype charac- terized by androgen signaling (LAR). They found that distinct gene ontologies are involved with each TNBC subtype as brief- ly described above. Furthermore, they identified TNBC cell lines representing these subtypes by using gene expression analysis. They generated preclinical evidence for the clinical application of TNBC subtyping by correlating driver signaling pathways with the results of in vitro drug response assays using pharmacologically targeted treatment, offering distinct gene signatures that could forecast an effective tailored treatment. These experiments showed that DNA damaging agents such as cisplatin are effective for the basal-like subtype, NVP-BEZ335 as an mammalian target of rapamycin (mTOR)-phosphati- dylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) co-inhibitor for the mesenchymal subtype, and bi- calutamide as an androgen receptor (AR) blockade for the LAR subtype.
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Targeted imaging and inhibition of triple-negative breast cancer metastases by a PDGFRβ aptamer

Targeted imaging and inhibition of triple-negative breast cancer metastases by a PDGFRβ aptamer

Platelet-derived growth factor receptor β (PDGFRβ) is a transmembrane receptor tyrosine kinase required for the mesenchymal lineage commitment during embryogenesis [7]. Its expression in normal adults is restricted to fibroblasts, vascular smooth muscle cells, endothelial and perivascular cells, where it plays important roles in wound healing and tissue repair, inflammation and angiogenesis [8]. It has been ascertained that overexpression of PDGFRβ in endothelial cells and tumor-associated stromal cells occurs in different human cancers, where PDGFRβ-dependent signaling contributes to angiogenesis and tumor progression [9-12]. More recently, PDGFRβ expression in cancer cells, mainly in populations characterized by a mesenchymal/stem and poorly differentiated phenotype, has been correlated with aggressiveness, resistance to therapy and/or recurrence in heterogeneous human cancers, including glioblastoma (GBM) [13, 14], colorectal cancer [15], tongue squamous cell carcinoma [16], medulloblastoma [17] and pancreatic neuroendocrine tumors [18]. Still, PDGFRβ has been shown to be a potent mediator of Foxq1-promoted stemness traits and chemoresistance in mammary epithelial cells [19] and its expression is induced during epithelial-to-mesenchymal transition (EMT) in breast cancer cells [20]. These experimental evidences suggest that the expression of PDGFRβ in breast cancer may be a unique feature of cancer cells that possess stem cell characteristics and/or that have undergone EMT, two features associated with chemoresistance and aggressiveness, thus encouraging therapeutic options in targeting this receptor. More recently, PDGFRβ has been shown to mediate endothelial cell differentiation of mesenchymal TNBC cells and vasculogenic mimicry (VM) [21].
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Triple negative breast cancer: shedding light onto the role of pi3k/akt/mtor pathway

Triple negative breast cancer: shedding light onto the role of pi3k/akt/mtor pathway

Since the PI3K/AKT pathway stabilizes the function of HR, Ibrahim and collaborators have demonstrated that the use of AKT inhibitors in TNBC cell lines without BRCA1/2 alterations could cause HR function changes, and then sensitize to PARPis. In particular, the study showed that TNBC cancer cells treated with buparlisib (AKT inhibitor) were subject to a subsequent hyperactivation of ERK and MEK1, two essential component of the MAP kinase signal transduction pathway, resulting in downregulation of BRCA1 and then favoring the action of olaparib (PARPi) with subsequent reduction of cell proliferation and survival [103]. An interesting in vitro study showed that targeting multiple kinases such as IGF-1R, PI3K, mTORC or MEK may suppress cell proliferation and induce apoptosis in MDA- MB-231 cells, increasing also the inhibition of Akt phosphorylation [104].
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An increased cell cycle gene network determines MEK and Akt inhibitor double resistance in triple-negative breast cancer

An increased cell cycle gene network determines MEK and Akt inhibitor double resistance in triple-negative breast cancer

Vera e. van der noord 1 , Ronan p. McLaughlin 1 , Marcel Smid 2 , John A. foekens 2 , John W. M. Martens 2 , Yinghui Zhang 1 & Bob van de Water 1 triple-negative breast cancer (tnBc) is an aggressive subtype of breast cancer with poor clinical prognosis and limited targeted treatment strategies. Kinase inhibitor screening of a panel of 20 TNBC cell lines uncovered three critical TNBC subgroups: 1) sensitive to only MEK inhibitors; 2) sensitive to only Akt inhibitors; 3) resistant to both MEK/Akt inhibitors. Using genomic, transcriptomic and proteomic datasets of these tnBc cell lines we unravelled molecular features associated with the MeK and Akt drug resistance. MeK inhibitor-resistant tnBc cell lines were discriminated from Akt inhibitor-resistant lines by the presence of PIK3CA/PIK3R1/PTEN mutations, high p-Akt and low p-MEK levels, yet these features could not distinguish double-resistant cells. Gene set enrichment analyses of transcriptomic and proteomic data of the MeK and Akt inhibitor response groups revealed a set of cell cycle-related genes associated with the double-resistant phenotype; these genes were overexpressed in a subset of breast cancer patients. cDK inhibitors targeting the cell cycle programme could overcome the Akt and MeK inhibitor double-resistance. in conclusion, we uncovered molecular features and alternative treatment strategies for tnBc that are double-resistant to Akt and MeK inhibitors.
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Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro

Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro

mTOR is a highly conserved serine/threonine protein kinase that belongs to the PI3K- related family and serves as a central regulator of cell metabolism, growth, proliferation and survival [8]. Extensive knowledge about the function of this protein has come from the experi- mental use of the natural bacterial antibiotic rapamycin, which inhibits the activity of mTOR. mTOR consists of two separate multi-protein complexes, mTORC1 and mTORC2, that are both activated by growth factor sti- mulation. The mTORC1 complex is rapamycin sensitive; rapamycin binds the FK506-binding protein (FKBP-12) which binds to and causes allosteric inhibition of the sig- nalling complex mTORC1 [9] which contains mTOR, the regulatory associated protein (RAPTOR), mLST8, PRAS40 and DEPTOR proteins. mTORC1 positively regulates protein translation and synthesis via its main substrates, p70 ribosomal S6 kinase (p70S6K) and the eukaryotic initiation factor 4E binding protein-1 (4E-BP1). Upon phosphorylation, 4E-BP1 dissociates from the mRNA cap-binding protein eIF4E and allows it to interact with eIF4G to form a translation initiation com- plex [10]. In the less well-defined rapamycin-insensitive mTORC2 complex [11], mTOR is associated with the rapamycin insensitive companion (RICTOR), LST8, mSIN1, PROCTOR and DEPTOR and phosphorylation of 4E-BP1 on t37/46 is also considered rapamycin insensitive [12]. The mTORC2 complex is involved in cytoskeletal organisation
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Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer

Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer

Disseminated triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options beyond chemotherapy. Therefore, identification of druggable vulnerabilities is an important aim. Protein kinases play a central role in cancer and particularly in TNBC. They are involved in many oncogenic functions including migration, proliferation, genetic stability or maintenance of stem-cell like properties. In this article we describe a novel multi-kinase inhibitor with antitumor activity in this cancer subtype. EC-70124 is a hybrid indolocarbazole analog obtained by combinatorial biosynthesis of Rebeccamycin and Staurosporine genes that showed antiproliferative effect and in vivo antitumoral activity. Biochemical experiments demonstrated the inhibition of the PI3K/mTOR and JAK/STAT pathways. EC-70124 mediated DNA damage leading to cell cycle arrest at the G2/M phase. Pathway analyses identified several deregulated functions including cell proliferation, migration, DNA damage, regulation of stem cell differentiation and reversion of the epithelial-mesenchymal transition (EMT) phenotype, among others. Combination studies showed a synergistic interaction of EC-70124 with docetaxel, and an enhanced activity in vivo. Furthermore, EC-70124 had a good pharmacokinetic profile. In conclusion these experiments demonstrate the antitumor activity of EC-70124 in TNBC paving the way for the future clinical development of this drug alone or in combination with chemotherapy.
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Patient derived xenografts of triple negative breast cancer reproduce molecular features of patient tumors and respond to mTOR inhibition

Patient derived xenografts of triple negative breast cancer reproduce molecular features of patient tumors and respond to mTOR inhibition

Introduction: Triple-negative breast cancer (TNBC) is aggressive and lacks targeted therapies. Phosphatidylinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways are frequently activated in TNBC patient tumors at the genome, gene expression and protein levels, and mTOR inhibitors have been shown to inhibit growth in TNBC cell lines. We describe a panel of patient-derived xenografts representing multiple TNBC subtypes and use them to test preclinical drug efficacy of two mTOR inhibitors, sirolimus (rapamycin) and temsirolimus (CCI-779). Methods: We generated a panel of seven patient-derived orthotopic xenografts from six primary TNBC tumors and one metastasis. Patient tumors and corresponding xenografts were compared by histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) sequencing; TNBC subtypes were determined. Using a previously published logistic regression approach, we generated a rapamycin response signature from Connectivity Map gene expression data and used it to predict rapamycin sensitivity in 1,401 human breast cancers of different intrinsic subtypes, prompting in vivo testing of mTOR inhibitors and doxorubicin in our TNBC xenografts.
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LncRNAs as new biomarkers to differentiate triple negative breast cancer from non-triple negative breast cancer

LncRNAs as new biomarkers to differentiate triple negative breast cancer from non-triple negative breast cancer

Triple negative breast cancer (TNBC) is an aggressive type of breast cancer with high heterogeneity. To date, there is no efficient therapy for TNBC patients and the prognosis is poor. It is urgent to find new biomarkers for the diagnosis of TNBC or efficient therapy targets. As an area of focus in the post-genome period, long non-coding RNAs (lncRNAs) have been found to play critical roles in many cancers, including TNBC. However, there is little information on differentially expressed lncRNAs between TNBC and non-TNBC. We detected the expression levels of lncRNAs in TNBC and non-TNBC tissues separately. Then we analyzed the lncRNA expression signature of TNBC relative to non-TNBC, and found dysregulated lncRNAs participated in important biological processes though Gene Ontology and Pathway analysis. Finally, we validated these lncRNA expression levels in breast cancer tissues and cells, and then confirmed that 4 lncRNAs (RP11-434D9.1, LINC00052, BC016831, and IGKV) were correlated with TNBC occurrence through receiver operating characteristic curve analysis. This study offers helpful information to understand the initiation and development mechanisms of TNBC comprehensively and suggests potential biomarkers for diagnosis or therapy targets for clinical treatment.
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<p>PIM-1 kinase: a potential biomarker of triple-negative breast cancer</p>

<p>PIM-1 kinase: a potential biomarker of triple-negative breast cancer</p>

gastric cancer, 11,63 oral squamous cell cancer, 64 colorectal cancer, 65 hepatocellular carcinoma, 66 bladder cancer, 67 and non-small cell lung cancer, 68,69 in addition to hematological malignancies. Secondly, dysregulation of PIM-1 has been associated with the invasiveness of cancer cells and patient prognosis. Although earlier studies suggested that upregu- lation of PIM-1 predicted favorable prognosis in patients with prostate cancer, 58 pancreatic cancer, 61 and non-small cell lung cancer, 69 overexpression of PIM-1 has been linked to increasing invasiveness and/or poor prognosis in a large number of cancers (Table 2). Furthermore, the mechanisms of PIM-1-induced tumorigenesis have been studied in great depth. E μ -Pim-1 transgenic mice overexpressing PIM-1 alone developed lymphoma with long latency and low incidence; 70 thus PIM-1 is considered to be a weak onco- gene. However, transgenic mice co-expressing PIM-1 and MYC succumbed to lymphomas in utero or around birth. 71 Moreover, MYC has been shown to induce tumorigenesis depending on the expression of PIM-1 kinase in lymphoma, prostate cancer, and breast cancer. 24,70,72,73 In prostate can- cer, PIM-1 phosphorylated the serine-62 of c-MYC to induce tumorigenesis, 73 while in breast cancer PIM-1 phos- phorylated p27 and BAD, in addition to MYC. 24 Furthermore, PIM-1 was also reported to phosphorylate AKT, facilitating the glycolysis of hepatocellular carcinoma and promoting tumor growth and metastasis. 66 These fi nd- ings suggest that PIM-1 may be involved in the develop- ment, progression, and maintenance of tumors via different mechanisms. This is consistent with the varied regulation of PIM-1 expression within different types of cells mentioned above. Of note, PIM-1 induced tumorigenesis in a variety of tumors, PIM-1 knockouts exerted only subtle effects with- out in fl uence on growth and reproduction, 74 and mice de fi - cient for all members of the PIM family (PIM-1, 2, 3) are Table 1 PIM-1 kinase substrates
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Inhibition of cyclin dependent kinase 9 by dinaciclib suppresses cyclin B1 expression and tumor growth in triple negative breast cancer

Inhibition of cyclin dependent kinase 9 by dinaciclib suppresses cyclin B1 expression and tumor growth in triple negative breast cancer

The effect of dinaciclib on MYC level through inhibition of CDK9 in MYC-driven tumor cells was reported previously in a study of B cell lymphoma cell lines [26]. Although dinaciclib was found to have a preferential growth inhibitory effect in MYC overexpressing TNBC cell lines [14], the dependency of MYC overexpressing TNBC on CDK1 was unclear. Our study confirmed the activity of dinaciclib in TNBC using PDX models and importantly, provided an explanation for the sensitivity of TNBC to dinaciclib and indicated that CDK9 inhibition as potential therapeutic strategy for MYC overexpressing TNBC. Selective CDK9 inhibitors are in preclinical and clinical development and impressive anti-tumor activity has been observed in chronic lymphocytic leukemia cell lines [48]. Studies of selective CDK9 inhibitors in TNBC are warranted. In addition, inhibitors against CDK7, which also plays an important role in phosphorylating the C-terminal domain of RNA polymerase II [49–51] and CDK9 [52], are being
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Targeted therapy in triple-negative metastatic breast cancer: a systematic review and meta-analysis

Targeted therapy in triple-negative metastatic breast cancer: a systematic review and meta-analysis

A broad search on the main computerized databases was conducted, including Embase, LILACS, Medline, Science Citation Index (SCI), CENTRAL, the National Cancer Institute Clinical Trials Service, and the Clinical Trials Register. In addition, the annual meeting proceedings of the American Society of Clinical Oncology, the San Antonio Breast Cancer Symposium, the American Association for Cancer Research, and the European Society for Medical Oncology were searched. The manufacturer of Bev in Brazil (Roche) was consulted about ongoing studies that had not yet been published or identified.
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Cisplatin-resistant triple-negative breast cancer subtypes: multiple mechanisms of resistance.

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

3 ). ABCC2 and GSR, specifically, represent a transporter and a glutathione metabolic enzyme, respectively, that lie in a pathway that detoxifies and transports cisplatin out of the cell [ 42 , 54 ]. The increase in ABCC2 and GSR, and their actions upstream of the cell death related genes, provides us with a testable hypothesis for an add- itional mechanism that contributes to the relative cis- platin resistance of the LAR subtype compared to the other subtypes. That is to say, inhibition of either or both of these proteins could make LAR cells more sensi- tive to cisplatin treatment (Fig. 4 ). AKT1, CLU and NQO1 encode proteins that respond to stress, including oxidative stress, which is one of the mechanisms of cis- platin action [ 70 ]. These three genes would contribute to cisplatin resitance in pathways downstream of GSR or ABCC2 [ 43 , 49 , 59 – 61 ]. BCL2L1 and CASP8 are both proteins integral to the apoptotic program. BCL2L1 is an inhibitor of apoptosis whose overexpression has been correlated with cisplatin-resistance, consistent with its upregulation in the resistant LAR subtype. The only down-regulated gene, MSH2, is a protein involved in DNA repair, although it has been shown to be necessary for the apoptotic action of cisplatin [ 56 , 57 ]. The up-
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TGF β inhibition enhances chemotherapy action against triple negative breast cancer

TGF β inhibition enhances chemotherapy action against triple negative breast cancer

Analysis of TGF-β gene expression signature. Raw Affy- metrix U133A array CEL files for the 51 breast can- cer cell lines were downloaded from ArrayExpress (E-TABM-157) and RMA normalized in R (http:// cran.r-project.org). Data were collapsed to the gene level by filtering duplicate Entrez IDs and by retaining only the most variable probe set for each gene. Genes present in a published TGF-β–induced signature in breast cancer cell lines (41) (TGF- β–responsive score [TBRS]) were extracted from the data and used for unsupervised hierarchical clustering (Spearman’s correlation with complete clustering) in R (http://cran.r-project.org). The molecular subtype of the cell lines was defined as described previously (42). For plotting, the signa- ture score was normalized across all cell lines to a Z score by subtracting the mean score and dividing by the standard deviation. NanoString gene expression analysis. Genes (n = 152) significantly regulated by TGF-β in 4 individual breast cell lines (41) were used to construct a TGF-β gene expression signature (TBRS). Genes upregulated (n = 101) and downregulated (n = 51) in this signature were quantified by NanoString in 17 paired breast tumors biopsied before and after neoadjuvant chemo- therapy. Data from 96 upregulated genes and 49 downregulated genes met quality controls and were available for analysis. The TGF-β signature score “s” was calculated as:
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Triple negative breast cancer: an Indian perspective

Triple negative breast cancer: an Indian perspective

Introduction: Breast cancer is the most common female cancer in the world. Triple negative breast cancer (TNBC) is a recently identified biological variant with aggressive tumor behav- ior and poor prognosis. Data of hormonal status from the Indian population is scarce due to financial constraints in performing immunohistochemistry evaluation. The present study aims to prospectively analyze receptor status of all breast cancer patients and identify TNBC and compare their clinical profile and short term survival with other non-TNBC group.
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Immunotherapeutic interventions of Triple Negative Breast Cancer

Immunotherapeutic interventions of Triple Negative Breast Cancer

protumourigenic effect from Tregs may serve as poten- tial immunotherapies similar to adoptive cell therapy (ACT). Moreover, the contents of the extracellular matrix (ECM), such as MMPs, prevalently change their activ- ity and show an association with cancer progression and thus serve as potential immunotherapeutic targets [9]. Tumour antigens comprise tumour-associated antigens (TAA) and tumour-specific antigens (TSA), which can be used to specifically detect neoplasms [4]. These anti- gens, especially TSA, can be harnessed as candidates for tumour-specific antibody treatments, chimeric antigen receptor cell therapies or antibody–drug conjugates to accurately target tumours. Still, there are many sophisti- cated mechanisms that regulate this process, such as the autocrine effect of T cells, and we should concentrate on the aspect that is helpful to tumours by way of immuno- therapy. Initial theories suggested that breast cancer (BC) is a non-immunogenic disease with fewer immunogenic tumour antigens [10], so BC has not been considered a cancer amenable to immunotherapeutic approaches for a long time; however, recent studies have shown evidence of significant immune cell infiltration of tumour-infiltrat- ing lymphocytes (TILs) in a subset of patient tumours and a consolidated understanding that Triple Negative Breast Cancer (TNBC) is a highly heterogeneous breast cancer subtype, with higher expression levels of PD-L1 and more TILs. The TIL score can be a prognostic and predictive marker in standard therapies. High numbers of TILs correlate with increased pathological complete responses to neoadjuvant chemotherapy in TNBC, which
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