Growth Of Human Breast Cancer Research Articles

The Marine Alga Sargassum horneri Is a Functional Food with High Bioactivity

Functional food factors can play a preventive and therapeutic role in several human diseases. The marine alga Sargassum horneri (S. horneri) has restorative effects in several types of metabolic disorders, including osteoporosis, diabetes, inflammatory conditions, and cancer cell growth. Osteoporosis is widely recognized as a major public health problem. Bone loss associated with ageing and diabetic states was prevented through the intake of bioactive compounds from S. horneri water extract in vivo by stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption in vitro. The intake of S. horneri water extract was found to have preventive effects on diabetic findings with an increase in serum glucose and lipid components. Furthermore, the S. horneri component has been shown to suppress adipogenesis from rat bone marrow cells and inflammatory conditions in vitro. Notably, the growth of bone metastatic human breast cancer MDA-MB-231 cells, which induce bone loss with osteolytic effects, was suppressed through culturing with the S. horneri water extract component in vitro. The S. horneri component, which has a molecular weight of less than 1000, was found to suppress the activation of NF-κB signaling by tumor necrosis factor-α, a cytokine associated with inflammation, in osteoblastic cells and macrophage RAW264.7 cells in vitro, suggesting a molecular mechanism. The bioactive component of S. horneri may play a multifunctional role in the prevention and treatment of metabolic disorders. This review outlines the advanced knowledge of the biological activity of the aqueous extract components of S. horneri and discusses the development of health supplements using this material.

Retracted] MicroRNA‑1297 contributes to tumor growth of human breast cancer by targeting PTEN/PI3K/AKT signaling.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the tumour images shown in Fig.7A and certain of the cell proliferation assay images shown in Fig.3B were strikingly similar to data that had already appeared in another article written by different authors at different research institutes [Xiao W Wang, J, LiH, XiaD, Yu G, Yao W, Yang Y, Xiao H, Lang B, Ma X et al: Fibulin‑1 is epigenetically down‑regulated and related with bladder cancer recurrence. BMC Cancer14: 677, 2014]. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncol Rep38: 2435‑2443, 2017; DOI: 10.3892/or.2017.5884].

In vitro cytotoxicity against breast cancer using biogenically synthesized gold and iron oxide nanoparticles derived from the hydroethanolic extract of Salvia officinalis L

Nanotechnology has a real-world impact on every aspect of life. Many researchers have been drawn to the biosynthesis of gold and iron oxide nanoparticles (Au-NPs and SPIONS) because they have a wide range of life applications. In this work, a single-step environmentally friendly biosynthesis of Au-NPs and SPIONS is reported by reducing solutions of gold aureate and ferric chloride is reported for the first time using the hydroethanolic extract (HEE) of Salvia officinalis (S. officinalis), an edible plant found in Egypt. The phytochemicals present in HEE were responsible for the reduction as well as stabilization of these nanoparticles. Before using the HEE, it was phytochemically screened for its constituents. Qualitatively, the HEE was found to have comparable levels of phenolics, flavonoids, tannins, proteins, carbohydrates, terpenoids, steroids, and polysaccharides. Quantitatively, total phenolics (236.91 ± 2.15 mg GAE/g extract), flavonoids (91.38 ± 0.97 mg QE/g extract), tannins (101.60 ± 1.33 mg/g extract), proteins (284.62 ± 2.65 mg/g extract), carbohydrates (127.73 ± 1.68 mg/g extract), soluble sugars (52.3 ± 0.67 mg/g extract), and polysaccharides (75.43 ± 1.01 mg/g extract) were estimated. In addition, HPLC analysis revealed the identification of seven phenolic compounds [ferulic (67.26%), chlorogenic (3.12%), caffeic (3.11%), p-coumaric (1.13%), protocatechuic (0.65%), catechin (0.69%), rosmarinic (0.53%)] and three flavonoids [apigenin (5.29%), quercetin-7-O-glucoside (3.39%), and luteolin-7-O-rutinose (2.01%)]. The characterization of the biosynthesized NPs was confirmed by Fourier transform infrared (FT-IR) spectroscopy, UV–Vis absorption spectroscopy, X-ray diffraction (XRD), and transmission electron microscopy (TEM). In vitro cytotoxic studies showed that Au-NPs, SPIONS, and HEE have an inhibitory effect on the growth of human breast cancer (MCF-7) cells at an IC50 of 6.53, 6.97, and 26.12 µg mL−1, respectively, by comparison with the standard drug (Doxorubicin) effect (0.18 µg mL−1).

Chitosan Nanoparticles Containing Cinnamomum verum J.Presl Essential Oil and Cinnamaldehyde; Preparation, Characterization and Anticancer Effects Against Melanoma and Breast Cancer Cells

Cancer is the second leading cause of death worldwide, and due to the emergence of resistance to synthetic drugs in different cancers, developing new green drugs have become crucial. In this study, chitosan nanoparticles containing Cinnamomum verum J.Presl essential oil and cinnamaldehyde (major ingredient) were first prepared. The obtained nanoparticles were then characterized using Dynamic Light Scattering (DLS), Transmission electron microscopy (TEM), and Attenuated Total Reflection-Fourier Transform InfraRed (ATR-FTIR). After that, anticancer effects of the as-prepared nanoparticles were investigated. IC50 values of chitosan nanoparticles containing the essential oil were observed at 79 and 112 µg/mL against A-375 and MDA-MB-468 cells, respectively. These values for chitosan nanoparticles containing cinnamaldehyde were obtained at 135 and 166 µg/mL. The results of the current study indicated that chitosan nanoparticles containing C. verum essential oil can inhibit the growth of human melanoma (A-375) and breast cancer (MDA-MB-468) cells.

The Effect of miR-4800 Restoration on Proliferation and Migration of Human Breast Cancer Cells In Vitro.

Purpose: MicroRNAs (miRNAs) can contribute to cancer initiation, development, and progression. In this study, the effect of miRNA-4800 restoration on the growth and migration inhibition of human breast cancer (BC) cells was investigated. Methods: For this purpose, transfection of miR-4800 was performed into MDA-MB-231 BC cells using jetPEI. Subsequently, the expression levels of miR-4800 and CXCR4, ROCK1, CD44, and vimentin genes were measured using quantitative real-time polymerase chain reaction (q-RT-PCR) and specific primers. Also, the proliferation inhibition and apoptosis induction of cancer cells were evaluated by MTT and flow cytometry (Annexin V-PI method) techniques, respectively. Additionally, cancer cell migration after miR-4800 transfection was assessed by wound-healing (scratch) assay. Results: The restoration of miR-4800 in MDA-MB-231 cells resulted in the decreased expression level of CXCR4 (P ˂ 0.01), ROCK1 (P ˂ 0.0001), CD44 (P ˂ 0.0001), and vimentin (P ˂ 0.0001) genes. Also, MTT results showed restoration of miR-4800 could significantly reduce cell viability rate (P ˂ 0.0001) compared with the control group. Cell migration remarkably inhibited (P ˂ 0.001) upon miR-4800 transfection in treated BC cells. Flow cytometry data demonstrated that miR-4800 replacement considerably induced apoptosis in cancer cells (P ˂ 0.001) compared with control cells. Conclusion: Taken together, it seems that miR-4800 can act as a tumor suppressor miRNA in BC and play an essential role in modulating apoptosis, migration, and metastasis in BC. Therefore, it may be suggested as a potential therapeutic target in treating BC by performing additional tests in the future.

Downregulation of the FBXO43 gene inhibits tumor growth in human breast cancer by limiting its interaction with PCNA

BackgroundThe function and regulatory mechanism of FBXO43 in breast cancer (BC) are still unclear. Here, we intended to determine the role and mechanism of FBXO43 in BC.MethodsFBXO43 expression in BC was evaluated by analysis of The Cancer Genome Atlas (TCGA). RT-qPCR and western blotting were utilized to detect FBXO43 expression in BC cell lines. Lentivirus was applied to downregulate FBXO43 in human BC cells. Proliferation assays were performed to evaluate the proliferative ability of BC cells. The apoptosis and cell cycle analysis of BC cells were analyzed by flow cytometry. Cell migration and invasion were investigated via Transwell assays. The function of FBXO43 in vivo was evaluated by constructing a xenograft mouse model. The proteins that might interact with FBXO43 in BC were identified by mass spectrometry, bioinformatics analysis, and co-immunoprecipitation (Co-IP) assays. Finally, rescue experiments were conducted to validate the recovery effects of the proteins interacting with FBXO43.ResultsFBXO43 was highly expressed in BC and was significantly downregulated after FBXO43 knockdown. The proliferation, migration, and invasion of BC cells were inhibited, and cell apoptosis was induced by FBXO43 knockdown. In addition, an in vivo experiment indicated that FBXO43 knockdown could inhibit the cell growth of BC. The results of the Co-IP assay showed that FBXO43 interacted with PCNA. Further rescue experiments confirmed that overexpression of PCNA significantly reversed the effects of FBXO43 knockdown on BC cells.ConclusionDownregulation of FBXO43 inhibits the tumor growth of BC by limiting its interaction with PCNA. FBXO43 might be a new potential oncogene and a therapeutic target for BC.

A Supramolecular Nanomedicine Based on Bendamustine and MDM2-Targeted D-peptide Inhibitor for Breast Cancer Therapy.

Bendamustine (BEN) is a FDA-approved bifunctional DNA-alkylating chemotherapy drug, but it suffers from short half-life, instability, and poor biocompatibility in the clinical application. Due to unique biostability of d-amino acid-containing peptides (D-peptides), constructing D-peptide-small molecule drug conjugates is emerging as a promising strategy for cancer therapy. Here, a high-affinity MDM2-targeted D-peptide (peptide 5) is discovered by applying structure-based drug design (SBDD). Taking the advantages of d-amino acids, a novel self-assembling D-peptide-small molecule drug conjugate (BEN-FF-peptide 5) is developed by simultaneously conjugating small molecule drug BEN and peptide 5 to the self-assembling peptide. In vitro results demonstrate that BEN-FF-peptide 5 exhibits superior cellular uptake ability, good biostability in human serum and strong inhibitory effect on the growth of human breast cancer (MCF-7) cells. In vivo study reveals that BEN-FF-peptide 5 significantly inhibits the growth of MCF-7 cells-derived xenograft in nude mice with no obvious side effects. This work provides a useful strategy to construct D-peptide-small molecule drug conjugates for high-efficacy and low-toxicity cancer therapy.

Structure-based discovery of potent and selective small-molecule inhibitors targeting signal transducer and activator of transcription 3 (STAT3).

STAT3 has been validated as an attractive anticancer target due to its important roles in cancer initiation and progression. However, discovery of potent and selective STAT3 small-molecule inhibitors with druglike properties is still challenging. In this study, two series of substituted 2-phenylquinolines and 2-arylimidazo[1,2-a]pyridines were designed through structure-based drug discovery approach by condensing the privileged structures of STX-119 and SH4-54. Our study has resulted in the discovery of a number of highly potent and selective STAT3 inhibitors, exemplified by compound 39 with the privileged structure of 2-phenylimidazo[1,2-a]pyridine, which selectively inhibits phosphorylation of STAT3 and suppresses subsequent signaling pathway. Moreover, 39 inhibits cell growth, migration and invasion of human triple negative breast cancer (TNBC) cells lines. Consistently, it achieves significant and dose-dependent tumor growth inhibition in both cell line-derived and patient-derived xenograft tumor models in mice. These results clearly indicate that 39 is a highly potent and selective STAT3 inhibitor.

Curcumin-Celecoxib: a synergistic and rationale combination chemotherapy for breast cancer.

Over-expression of COX-2 has been linked with various molecular signaling such as carcinogenesis, invasiveness, and malignant tumour metastasis. Besides, the use of celecoxib is also related to lowering the risk of breast cancer. This study therefore designed to explore the synergistic inhibitory effect of the combination of curcumin and celecoxib on the growth of human breast cancer cells. In our investigation, we treated MDA-MB-231 cancer cells with different concentrations of curcumin and celecoxib. The enzyme-linked immunoassay was used to measure the COX-2 expression levels. MDA-MB-231 growth was examined by MTS cell viability assay, and synergy detection was carried out using combination index approaches. The drug-likeliness of the tested drugs (curcumin and celecoxib) were computed and predicted ADME pharmacokinetic parameters by in silico. Further, we have conducted BOILED-Egg plot and bioavailability radar analysis for the curcumin and celecoxib. The result of the physicochemical and ADMET/pharmacokinetic properties showed that these two drugs have good oral and optically bioavailable absorption. The present in silico study could offer a reliable theoretical basis for future structural modification of these compounds to treat breast cancer. The in vitro results suggested that curcumin and celecoxib individually inhibited the growth of MDA-MB-231 cells in a dose-dependent manner. The effect was synergistic for MDA-MB-231 cells relative to the two compounds individually. The synergistic growth inhibitory effect was mediated by a mechanism that possibly involves inhibition of the COX-2 pathways. Our findings show the prominent anti-proliferative effects of celecoxib and/or curcumin on MDA-MB-231 cells, providing a rationale for further detailed preclinical and potential clinical studies of this combination for breast cancer therapy. Further, these computed parameters suggested that curcumin possesses a high tendency to act as an adjuvant drug with celecoxib in the treatment of breast cancer.

Two novel chiral tetranucleate copper-based complexes: syntheses, crystal structures, inhibition of angiogenesis and the growth of human breast cancer in vitro and in vivo.

The single crystals of two novel chiral tetranucleate copper(II)-based complexes (TNCu-A and TNCu-B) containing L-methioninol-derived Schiff-bases were obtained. Their single structures were characterized by X-ray single crystal diffraction, infrared (IR) rays, elemental analysis, and liquid chromatography-mass spectrometry analysis. TNCu-A can effectively inhibit human umbilical vein endothelial cells (HUVECs) to form a tubular structure and it induces apoptosis of human triple-negative breast cancer MDA-MB-231 cells and HUVECs in vitro in a mitochondria dependent manner. Moreover, in vivo TNCu-A can remarkably inhibit the growth of triple-negative breast cancer from which MDA-MB-231 cells were xenografted into severely immunodeficient nude mice by inhibiting proliferation, inducing apoptosis of MDA-MB-231 cells by dramatically inhibiting the expression of the anti-apoptotic protein Bcl-2 and up-regulating the expressions of proapoptotic proteins caspase-9 and Bax, and simultaneously inhibiting tumor angiogenesis by decreasing the density of vascular endothelial cells and suppressing migration and even partially inducing apoptosis.

Verminoside from Pseudolysimachion rotundum var. subintegrum sensitizes cisplatin-resistant cancer cells and suppresses metastatic growth of human breast cancer

Breast cancer is one of the most common cancers in women and is associated with a high mortality rate. The majority of deaths resulting from breast cancer are attributable to metastatic growth; in addition, chemoresistance is a major concern in the treatment of patients with breast cancer. However, limited drugs are available for the treatment of metastatic breast cancer. In this study, the chemoadjuvant effects of a methanolic extract from the leaves of Pseudolysimachion rotundum var. subintegrum (NC13) and an active component isolated from the plant, verminoside (Vms), were evaluated. Furthermore, their potent anti-metastatic activities were validated in vitro and in vivo in animal models. The anti-metastatic and chemosensitizing activities of NC13 and Vms on cisplatin treatment were found to be partly mediated by suppression of the epithelial–mesenchymal transition of cancer cells. Collectively, our results implied that NC13 and its bioactive component Vms could be developed as effective chemoadjuvants in combination with conventional therapeutics.

Long noncoding RNA MEG3 suppresses cell proliferation, migration and invasion, induces apoptosis and paclitaxel-resistance via miR-4513/PBLD axis in breast cancer cells

ABSTRACT Breast cancer remains a general-threat event in the health of women. Currently, increasing records indicate that long non-coding RNA maternally expressed 3 (MEG3) plays a central role in breast cancer. The current research focused on the function of MEG3 in paclitaxel (PTX)-resistance and human breast cancer growth. Levels of MEG3, microRNA (miR)-4513, and phenazine biosynthesis-like domain-containing protein (PBLD) were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assays. 3-(4.5-dimethylghiazol-2-yl)-2,5-diphenyltetrazolium Bromide (MTT) assay was performed to examine the IC50 of PTX and cell proliferation in breast cancer cells. In addition, cell apoptosis was determined utilizing flow cytometry. Transwell was conducted to assay cell migration and invasion in MCF-7 and MDA-MB-231 cells. The interaction between miR-4513 and MEG3 or PBLD was expounded via dual-luciferase reporter assay. Levels of MEG3 and PBLD were decreased, but miR-4513 level was triggered in breast cancer tissues and cell lines. Overexpression of MEG3 could reinforce cell apoptosis, impede proliferation, migration, invasion, and the IC50 of PTX in breast cancer cells. Moreover, the impact of miR-4513 inhibitor on cell progression and PTX-resistance was overturned by MEG3 deficiency. Interestingly, miR-4513 mimic could abolish the role of PBLD upregulation in cell behaviors and PTX-resistance in MCF-7 and MDA-MB-231 cells. Finally, the expression of PBLD was co-modulated by miR-4513 and MEG3 in vitro. MEG3/miR-4513/PBLD axis modulated PTX-resistance and the development of breast cancer cells, which might provide a promising therapeutic strategy for breast cancer.

Estrogens Determine Adherens Junction Organization and E-Cadherin Clustering in Breast Cancer Cells via Amphiregulin.

SummaryEstrogens play an important role in the development and progression of human cancers, particularly in breast cancer. Breast cancer progression depends on the malignant destabilization of adherens junctions (AJs) and disruption of tissue integrity. We found that estrogen receptor alpha (ERα) inhibition led to a striking spatial reorganization of AJs and microclustering of E-Cadherin (E-Cad) in the cell membrane of breast cancer cells. This resulted in increased stability of AJs and cell stiffness and a reduction of cell motility. These effects were actomyosin-dependent and reversible by estrogens. Detailed investigations showed that the ERα target gene and epidermal growth factor receptor (EGFR) ligand Amphiregulin (AREG) essentially regulates AJ reorganization and E-Cad microclustering. Our results not only describe a biological mechanism for the organization of AJs and the modulation of mechanical properties of cells but also provide a new perspective on how estrogens and anti-estrogens might influence the formation of breast tumors.

Important role of annexin A2 (ANXA2) in new blood vessel development in vivo and human triple negative breast cancer (TNBC) growth

Development of new blood vessels in the tumor microenvironment is an essential component of tumor progression during which newly formed blood vessels nourish tumor cells and play a critical role in rapid tumor growth, invasion and metastasis. Nevertheless, how tumor cells develop new blood vessels in the tumor microenvironment (TME) have been enigmatic. Previously, we have shown specific overexpression of ANX A2 in TNBC cells regulates plasmin generation and suspected a role in neoangiogenesis. In this report, we used Matrigel plug model of in vivo angiogenesis and confirmed its role in new blood vessel development. Next, we tested if blocking of ANX A2 in aggressive human breast TME can inhibit angiogenesis and tumor growth in vivo. We showed that aggressive human breast tumor cells growing in nude mice can induce intense neoangiogenesis in the tumor mass. Blocking of ANXA2 significantly inhibited neoangiogenesis and resulted in inhibition of tumor growth. Interestingly, we identified that blocking of ANXA2 significantly inhibited tyrosine phosphorylation (Tyr-P) of ANXA2 implying its involvement in tyrosine signaling pathway and suggesting it may regulate angiogenesis. Taken together, our experimental evidence suggests that ANX A2 could be a novel strategy for disruption of tyrosine signaling and inhibition of neoangiogenesis in breast tumor.

Abstract 1154: AFPep mitigates the risk of breast cancer

Abstract Women whose risk of breast cancer is elevated (based on Gail or Tyrer-Cuzik models) have only limited options to intervene in attempt to alter disease progression, and most options are of limited efficacy or have unwanted side effects. Options include increased surveillance, lifestyle changes, drugs such as tamoxifen or aromatase inhibitors, or removal of target tissue. Options that are more efficacious, better tolerated, and more empowering are needed for women in high-risk cohorts. For this purpose, we have developed AFPep, a homobiotic, selective anti-estrogenic/anti-breast cancer active site-analog of alpha-fetoprotein (AFP). AFPep stops growth of human breast cancers growing in xenograft models and prevents development of either estrogen-induced or MNU-induced mammary cancers in rats. In all models, AFPep is effective against tamoxifen-resistant breast cancer, is additive with tamoxifen (allowing dose reduction of tamoxifen), and reduces the uterine hyperplasia induced by tamoxifen. AFPep does not disrupt the estrous cycle of rats, nor does it alter fertility or fecundity and does not induce teratogenicity. The mechanism of action of AFPep differs from that of tamoxifen in that AFPep inhibits phosphorylation of the estrogen receptor leading to a downstream biomarker profile consistent with inhibition of tumor growth. AFPep is orally bioavailable and well tolerated in mice, rats, dogs and primates. The therapeutic index of AFPep in rats shows a substantially broader safety margin than that of currently used agents. AFPep may offer an effective, well tolerated option for women in high risk cohorts who wish to mitigate their risk of breast cancer. Citation Format: Samuel B. Fordyce, Thomas T. Andersen, James A. Bennett. AFPep mitigates the risk of breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1154.

Biologic Drug Quality Assurance to Optimize HER2 + Breast Cancer Treatment: Insights from Development of the Trastuzumab Biosimilar SB3.

SB3 is a biosimilar of trastuzumab that has been approved for use in the treatment of human epidermal growth factor 2-positive breast cancer and human epidermal growth factor 2-positive gastric cancer. Antibody-dependent cellular cytotoxicity is one of several critical quality attributes of trastuzumab. Data from the development of SB3 support the hypothesis of a relationship between antibody-dependent cellular cytotoxicity activity and clinical outcomes in terms of the response rate and long-term survival. Current analytic methods utilizing advanced technology allow the detection of small changes in other quality attributes that influence antibody-dependent cellular cytotoxicity, such as glycosylation and FcγRIIIa binding. Use of such methods to monitor batch-to-batch consistency enables production of trastuzumab biosimilars with consistent quality. Trastuzumab biosimilars such as SB3 therefore have the potential to increase accessibility to trastuzumab-based therapy without compromising efficacy or safety.

Pharmacological disruption of the Notch transcription factor complex

Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.

Graphdiyne-templated palladium-nanoparticle assembly as a robust oxygen generator to attenuate tumor hypoxia

Abstract Nanocatalysts have attracted many concerns in biomedical fields because their catalytic performance is robust and remains efficient even at a harsh condition compared to biological enzymes. However, the stability for both physical forms and the catalytic activity are the main challenges during biomedical applications. Here, we described a strategy to prepare a stable nanocatalyst that two-dimensional (2D) graphdiyne (GDY) serves as a template to immobilize catalytic palladium nanoparticles (PdNPs) on the GDY surface. In the presence of H2O2, the PdNPs/GDY composite functions as an oxygen generator to decompose H2O2 to produce molecular oxygen, which efficiently attenuates tumor hypoxia and delays tumor growth. According to X-ray absorption spectroscopy and computational simulation, we revealed that PdNPs mainly contribute to the decomposition of H2O2 into O2 companying with the variation in chemical forms of Pd in the presence of H2O2. Importantly, 2D GDY firmly anchors and disperses ultra-small PdNPs on the surface via Pd-C bonds to prevent the oxidation and aggregation of PdNPs that realizes sustainable and stable catalysis. This design endows the highly immobilized content of Pd on GDY, high catalytic activity and higher stability in catalytic reaction than commercial Pd/C and PdNPs/GO, accordingly. The PdNPs/GDY composite also exhibits as an effective and durable oxygen generator to decompose endogenous H2O2 and produces O2 inside solid tumors, attenuates tumor hypoxia, down-regulates HIF-1α expression and ultimately delays tumor growth in both human patient-derived squamous cell lung carcinoma xenograft model and 4T1 breast cancer xenografted mouse model. Moreover, in the combination with the chemotherapeutic agent, doxorubicin, PdNPs/GDY-based catalytic therapy achieved a significantly enhanced antitumor effect. Our findings demonstrate that the rational design of a nano-modulator for tumor hypoxia with long term stability is a promising way to enhance the outcome of tumor therapy.

A novel 4-aminoquinazoline derivative, DHW-208, suppresses the growth of human breast cancer cells by targeting the PI3K/AKT/mTOR pathway

Breast cancer is one of the most frequent cancers among women worldwide. However, there is still no effective therapeutic strategy for advanced breast cancer that has metastasized. Aberrant activation of the PI3K/AKT/mTOR pathway is an essential step for the growth of human breast cancers. In our previous study, we designed and synthesized DHW-208 (2,4-difluoro-N-(5-(4-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)quinazolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide) as a novel pan-PI3K inhibitor. This study aimed to assess the therapeutic efficacy of DHW-208 in breast cancer and investigate its underlying mechanism. We found that DHW-208 inhibited the growth, proliferation, migration, and invasion of breast cancer cells. Moreover, DHW-208 induced breast cancer cell apoptosis via the mitochondrial pathway and induced G0/G1 cell-cycle arrest. In vitro results show that DHW-208 is a dual inhibitor of PI3K and mTOR, and suppress the growth of human breast cancer cells by targeting the PI3K/AKT/mTOR pathway. Consistent with the in vitro results, in vivo studies demonstrated that DHW-208 elicits an antitumor effect by inhibiting the PI3K/AKT/mTOR-signaling pathway with a high degree of safety in breast cancer. Above all, we report for the first time that DHW-208 suppressed the growth of human breast cancer cells by inhibiting the PI3K/AKT/mTOR-signaling pathway both in vivo and in vitro. Our study may provide evidence for the use of DHW-208 as an effective, novel therapeutic candidate for the treatment of human breast cancers in clinical trials.

Subcellular partitioning of Kaiso (ZBTB33) as a biomarker to predict overall breast cancer survival.

3534 Background: The epigenetic transcriptional regulator, Kaiso (ZBTB33) has been identified as a member of the C2H2 zinc finger proteins containing a BTB/POZ -zinc finger family of transcription factors that are implicated in development of cancer. Although, our understanding of clinical relevance of subcellular distribution (cytoplasmic/nuclear) Kaiso in the growth and survival of human Breast cancer (BC) is limited. Methods: We examined a cohort of 555 BC patients who underwent surgery for their primary BC in Greenville, NC using AI and SM approach. Results: The sub-classification BC shows, cytoplasmic Kaiso is differentially enriched in ER- BC (p=0.001) compared nuclear Kaiso (p=0.8) and is significantly enriched in the more aggressive classes LumB (p=0.0017), HER2+ (p=0.05) and TNBC (p=6.1e-07) with respect to LumA BC patients. Additionally, the survival analysis of different compartments of Kaiso demonstrates that high cytoplasmic Kaiso (HR = 16.29 (7.6 – 34.8), p = 5.5e−13) is much more predictive of poor survival compared to nuclear Kaiso (HR = 2.83 (2.02 – 3.8), p = 6.1e−11). At gene expression level, ZBTB33 mRNA levels do not correlate with either nuclear (Spearman correlation: -0.03157, p= 0.7267) or cytoplasmic levels (Spearman correlation: -0.03526, p= 0.6962) of Kaiso. Surprisingly, ZBTB33 mRNA abundance is predictive of poor overall BC survival as demonstrated in two independent publicly available BC cohorts Metabric (HR = 2.14 (1.49 − 3.08), p = 2.7e−05) and Gyorffy B et al. (HR = 1.81 (1.55 − 2.12), p = 2.5e−14). Nuclear and cytoplasmic levels of Kaiso do not show significant differences based on race p=0.27 and p=0.1 respectively. Conclusions: Our data suggest subcellular distribution of high Kaiso is associated with poor prognosis of BC survival and subcellular localizations of Kaiso may play differential biological roles in BC prognosis.