Novel quinuclidinone derivatives induced apoptosis in human breast cancer via targeting p53

Small molecules that can target human cancers have been highly sought to increase the anticancer efficacy, the present work describes the design and synthesis of novel series of five quinuclidinone derivatives (2a-2e). Their anticancer activities were investigated against breast cancer cells MCF-7, MDA-MB-231 breast cancer cells harboring mutant p53 and normal breast counterpart MCF-12a. Derivative 2e reduced proliferation of MCF-7 and MCF-12a while it has no effect on MDA-MB-231. Derivative 2e induced apoptosis in MCF-7 cells which is further confirmed by TUNEL assay and it reduced the percentage of cell in G2/M phase as confirmed by increased expression of cyclin B and reduced expression of cyclin D1. Derivative 2e reduced expression levels of Mdm2, Akt and ERK1/2 by and increased expression level of p53. Moreover, the apoptosis induction by 2e was also inhibited by PFT-α as evidenced by non-significant induction of apoptosis after treatment of MCF-7 cells with both derivative 2e and PFT-α. In addition, docking study reveals that derivative 2e has a binding pattern close to the pattern observed in the structure of the lead fragment 5,6-dimethoxy-2-methylbenzothiazole bound to T-p53C-Y220C. The above findings demonstrate that derivative 2e induces apoptosis in MCF-7 cells via targeting p53 which merits further development.     

3-Acyl-5-hydroxybenzofuran derivatives as potential anti-estrogen breast cancer agents: A combined experimental and theoretical investigation

We first report the application of 3-acyl-5-hydroxybenzofurans as a scaffold to develop potential drugs for breast cancer. Seven novel derivative compounds were synthesized by using a microwave-assisted synthesis method. Those compounds exhibited different antiproliferation against human breast cancer MCF-7 cells, with the best activity of IC₅₀ = 43.08 μM for compound 1. A Quantum Mechanics Polarized Ligand Docking (QPLD) study was carried out to investigate the binding interactions between these compounds and estrogen receptor alpha (ERα). The simulation results showed that the trend of receptor–ligand binding interactions was same as that of their antiproliferative activities. A detailed analysis indicated that compound 1 possesses the highest Van der Waals and hydrogen bond interactions compared to the other six compounds and better inhibitors are achievable by enhancing the hydrogen bond interactions. Based on these results, we addressed that 3-acyl-5-hydroxybenzofuran is an attractive scaffold for designing drugs against breast cancer.     

A Monte Carlo analysis of breast screening randomized trials

PurposeTo analyze breast screening randomized trials with a Monte Carlo simulation tool.MethodsA simulation tool previously developed to simulate breast screening programmes was adapted for that purpose. The history of women participating in the trials was simulated, including a model for survival after local treatment of invasive cancers. Distributions of time gained due to screening detection against symptomatic detection and the overall screening sensitivity were used as inputs. Several randomized controlled trials were simulated. Except for the age range of women involved, all simulations used the same population characteristics and this permitted to analyze their external validity. The relative risks obtained were compared to those quoted for the trials, whose internal validity was addressed by further investigating the reasons of the disagreements observed.ResultsThe Monte Carlo simulations produce results that are in good agreement with most of the randomized trials analyzed, thus indicating their methodological quality and external validity. A reduction of the breast cancer mortality around 20% appears to be a reasonable value according to the results of the trials that are methodologically correct. Discrepancies observed with Canada I and II trials may be attributed to a low mammography quality and some methodological problems. Kopparberg trial appears to show a low methodological quality.ConclusionMonte Carlo simulations are a powerful tool to investigate breast screening controlled randomized trials, helping to establish those whose results are reliable enough to be extrapolated to other populations and to design the trial strategies and, eventually, adapting them during their development.     

Network Analysis Reveals A Signaling Regulatory Loop in the PIK3CA-mutated Breast Cancer Predicting Survival Outcome

Mutated genes are rarely common even in the same pathological type between cancer patients and as such, it has been very challenging to interpret genome sequencing data and difficult to predict clinical outcomes. PIK3CA is one of a few genes whose mutations are relatively popular in tumors. For example, more than 46.6% of luminal-A breast cancer samples have PIK3CA mutated, whereas only 35.5% of all breast cancer samples contain PIK3CA mutations. To understand the function of PIK3CA mutations in luminal A breast cancer, we applied our recently-proposed Cancer Hallmark Network Framework to investigate the network motifs in the PIK3CA-mutated luminal A tumors. We found that more than 70% of the PIK3CA-mutated luminal A tumors contain a positive regulatory loop where a master regulator (PDGF-D), a second regulator (FLT1) and an output node (SHC1) work together. Importantly, we found the luminal A breast cancer patients harboring the PIK3CA mutation and this positive regulatory loop in their tumors have significantly longer survival than those harboring PIK3CA mutation only in their tumors. These findings suggest that the underlying molecular mechanism of PIK3CA mutations in luminal A patients can participate in a positive regulatory loop, and furthermore the positive regulatory loop (PDGF-D/FLT1/SHC1) has a predictive power for the survival of the PIK3CA-mutated luminal A patients.     

CCN5/WISP-2: A micromanager of breast cancer progression

The gain of plasticity by a subset of cancer cells is a unique but common sequence of cancer progression from epithelial phenotype to mesenchymal phenotype (EMT) that is followed by migration, invasion and metastasis to a distant organ, and drug resistance. Despite multiple studies, it is still unclear how cancer cells regulate plasticity. Recent studies from our laboratory and others’ proposed that CCN5/WISP-2, which is found intracellularly (in the nucleus and cytoplasm) and extracellularly, plays a negative regulator of plasticity. It prevents the EMT process in breast cancer cells as well as pancreatic cancer cells. Multiple genetic insults, including the gain of p53 mutations that accumulate over the time, may perturb CCN5 expression in non-invasive breast cancer cells, which ultimately helps cells to gain invasive phenotypes. Moreover, emerging evidence indicates that several oncogenic lesions such as miR-10b upregulation and activation of TGF-β-signaling can accumulate during CCN5 crisis in breast cancer cells. Collectively, these studies indicate that loss of CCN5 activity may promote breast cancer progression; application of CCN5 protein may represent a novel therapeutic intervention in breast cancer and possibly pancreatic cancer.     

基于网络药理学的谷糠结合态多酚抗乳腺癌机制研究

本研究旨在探讨谷糠结合态多酚(bound phenol of inner shell,BPIS)发挥抗乳腺癌细胞活性的作用机制。首先采用细胞计数法检测BPIS对乳腺癌细胞以及正常乳腺细胞活性的影响;然后综合运用SEA、SIB以及GeneCards等数据库获得BPIS和乳腺癌的相关靶点,并分析活性成分与作用靶点的互作网络以及通路。本研究筛选得到BPIS抗乳腺癌相关靶点39个,主要涉及糖脂代谢和细胞自噬等生物过程以及MAPK、PI3K/AKT、FoxO等多条信号通,表明BPIS抗乳腺癌是多成分、多靶点、多通路协同作用的过程,而与细胞死亡相关的细胞自噬很可能在BPIS抑制乳腺癌过程中发挥主要作用。     

microRNA-1298 inhibits the malignant behaviors of breast cancer cells via targeting ADAM9

MicroRNAs (miRNAs) regulate the progression of human malignancy by targeting oncogenes or tumor suppressors, which are 12 promising targets for cancer treatment. Increasing evidence has suggested the aberrant expression and tumor-suppressive function of miR-1298 in cancers, however, the regulatory mechanism of miR-1298 in breast cancer (BC) remains unclear. Here, our findings showed that miR-1298 was down-regulated in BC tissues and cell lines. Lower level of miR-1298 was significantly correlated with the advanced progression of BC patients. Experimental study showed that overexpression of miR-1298 inhibited the proliferation, induced apoptosis and cell cycle arrest in BC cells. The in vivo xenograft mice model showed that highly expressed miR-1298 significantly reduced the tumor growth and metastasis. Further mechanism analysis revealed that miR-1298 bound the 3′-untranslated region (UTR) of a disintegrin and metalloproteinase 9 domain (ADAM9) and suppressed the expression of ADAM9 in BC cells. ADAM9 was overexpressed in BC tissues and inversely correlated with miR-1298. Down-regulation of ADAM9 induced apoptosis and cell cycle arrest of BC cells. Moreover, ectopic expression of ADAM9 by transiently transfecting with vector encoding the full coding sequence of ADAM9 attenuated the inhibitory effects of miR-1298 on the proliferation and cell cycle progression of BC cells. Collectively, our results illustrated that miR-1298 played a suppressive role in regulating the phenotype of BC cells through directly repressing ADAM9, suggesting the potential application of miR-1298 in the therapy of BC.     

A novel mouse monoclonal antibody targeting ErbB2 suppresses breast cancer growth

Overexpression of ErbB2 in breast cancer is associated with increased recurrence and worse prognosis. Accumulating evidences suggest that molecular targeted therapy is a promising anticancer strategy. In this study, we produced a novel anti-ErbB2 monoclonal antibody, 6G10, that recognized an epitope distinct from the trastuzumab binding site. 6G10 induced aggregation of BT474 breast cancer cells and inhibited proliferation of various breast cancer cell lines including BT474. A growth inhibition assay showed that 6G10 had EC₅₀ values comparable to trastuzumab, indicating that the drugs have a similar level of potency. Furthermore, intraperitoneal administration of 6G10 completely inhibited the growth of xenografted tumors derived from BT474 and SK-BR-3 cells. These data suggested that 6G10 has great therapeutic potential and could be administered to patients alternatively, or synergistically, with trastuzumab.     

Lobular ectopic breast carcinoma: A case-report

In about 1–2% of the population an incomplete regression of the embryonic mammary line occurs, which may result in the presence of ectopic breast tissue. An ectopic breast tissue carcinoma is a rare entity. The authors present a case-report of a 51-year-old female patient, with a lobular carcinoma in an axillary ectopic breast tissue submitted to surgery and adjuvant radiotherapy.     

Probing the human estrogen receptor-α binding requirements for phenolic mono- and di-hydroxyl compounds: A combined synthesis,binding and docking study

Various estrogen analogs were synthesized and tested for binding to human ERα using a fluorescence polarization displacement assay. Binding affinity and orientation were also predicted using docking calculations. Docking was able to accurately predict relative binding affinity and orientation for estradiol, but only if a tightly bound water molecule bridging Arg394/Glu353 is present. Di-hydroxyl compounds sometimes bind in two orientations, which are flipped in terms of relative positioning of their hydroxyl groups. Di-hydroxyl compounds were predicted to bind with their aliphatic hydroxyl group interacting with His524 in ERα. One nonsteroid-based dihdroxyl compound was 1000-fold specific for ERβ over ERα, and was also 25-fold specific for agonist ERβ versus antagonist activity. Docking predictions suggest this specificity may be due to interaction of the aliphatic hydroxyl with His475 in the agonist form of ERβ, versus with Thr299 in the antagonist form. But, the presence of this aliphatic hydroxyl is not required in all compounds, since mono-hydroxyl (phenolic) compounds bind ERα with high affinity, via hydroxyl hydrogen bonding interactions with the ERα Arg394/Glu353/water triad, and van der Waals interactions with the rest of the molecule.     

Trends in breast and cervical cancer in India under National Cancer Registry Programme: An Age-Period-Cohort analysis

BackgroundTrend analysis in cancer quantifies the incidence rate and explains the trend and pattern. Breast and cervical cancers are the two most common cancers among Indian women which contributed 39.4 % to the total cancer in India for the year 2020. This study aimed to report the time trends in cancer incidence of breast and cervical cancer using Age–Period–Cohort (APC) model from five Population Based Cancer Registries (PBCRs) in India for the period of 1985–2014.MethodAge-Period-Cohort model was fitted to five PBCRs of Bangalore, Chennai, Delhi, Bhopal and Barshi rural for breast and cervical cancer for 25−74 age-groups. The Estimated Annual Percent Change (EAPC) was calculated. Rate Ratio (RR) of cohort effects were estimated with a constraint of period slope to be zero (p = 0) since cohort has a stronger association with incidence than period.ResultA significant increase was noted in breast cancer in all PBCRs (EAPC, Range: Delhi, 1.2 % to Bangalore, 2.7 %) while significant decrease in cervical cancer (EAPC, Range: Bangalore -2.5 % to Chennai, -4.6 %) from all the PBCRs including Barshi rural during the period. RR estimates for breast cancer showed increasing trend whereas cervical cancer showed decreasing trend in successive birth cohorts across all five PBCRs.ConclusionIn both breast and cervical cancers, a significant age, cohort and period effect was noted in Bangalore, Chennai and Delhi. Despite period effect, the cohort effect was predominant and it may be attributed to the generational changes in risk factors among cancer breast and cervix.     

Primary squamous cell carcinoma of the breast: A rare case report

BackgroundSquamous cells are normally not found inside the breast. Therefore, a primary squamous cell carcinoma of the breast is an exceptional phenomenon and the management of this type of disease is still debated.AimClinical outcome assessment of a patient with squamous cell carcinoma of the breast.Materials and methodsWe report a case of primary squamous cell carcinoma of the breast (T1cN0M0) in a 51-years-old woman who underwent breast conserving surgery plus adjuvant chemotherapy and radiation therapy (RT).ResultsWith a follow up of 43 months, the patient is alive with no evidence of local or distant recurrence. The patient had Grade 2 acute skin toxicity. No late skin or respiratory toxicity was observed.ConclusionsPure primary squamous cell carcinoma of the breast is a rare and aggressive disease, often treatment-refractory. Our case shows that the addition of RT after breast conserving surgery, allows to achieve a high local control without adding severe toxicity. A multidisciplinary approach seems to be the optimal management for early stages in this rare disease.     

Tailor-making of protein drugs by polymer conjugation for tumor targeting: A brief review on smancs

Chemical conjugation of poly(styrene-co-maleic acid) to an antitumor protein (neocarzinostatin) yielded an entirely new derivative designated as smancs (polystyrene-maleic acid conjugated neocarzinostatin). The purpose of the modification was to improve its pharmacological properties; the resulting conjugate exhibited much higher tumoritropism and lymphotropism, enhancedin vivo stability (about ten times), higher chemotherapeutic index (lower toxicity), and decreased antigenicity. Another advantage associated with this molecular engineering was an increased hydrophobicity. By this character it was solubilized in lipid contrast medium Lipiodol^R, which facilitated highly sensitive detection under x-ray-accompanying selective anticancer effectin situ. Three factors were responsible for such improvements: molecular size, hydrophobicity, and polyanionic nature. Most of the known drugs so far used as therapeutic agents are less than 1000 daltons, and those with larger molecular weights have been explored much less extensively. By polymer conjugation, the size of the drug can be extended to about 15,000 daltons (macromolecular therapeutics). The most outstanding characteristic of smancs (16,000 daltons) was the tumoritropicity, which may be a result of the highly developed neovasculature of solid tumors. Smancs as a prototype drug thus appears to lead the way in cancer drug targeting.     

Accuracy and completeness of the New Zealand Cancer Registry for staging of invasive breast cancer

PurposePopulation based cancer registries are an invaluable resource for monitoring incidence and mortality for many types of cancer. Research and healthcare decisions based on cancer registry data rely on the case completeness and accuracy of recorded data. This study was aimed at assessing completeness and accuracy of breast cancer staging data in the New Zealand Cancer Registry (NZCR) against a regional breast cancer register.MethodologyData from 2562 women diagnosed with invasive primary breast cancer between 1999 and 2011 included in the Waikato Breast Cancer Register (WBCR) were used to audit data held on the same individuals by the NZCR. WBCR data were treated as the benchmark.ResultsOf 2562 cancers, 315(12.3%) were unstaged in the NZCR. For cancers with a known stage in the NZCR, staging accuracy was 94.4%. Lower staging accuracies of 74% and 84% were noted for metastatic and locally invasive (involving skin or chest wall) cancers, respectively, compared with localized (97%) and lymph node positive (94%) cancers. Older age (>80 years), not undergoing therapeutic surgery and higher comorbidity score were significantly (p < 0.01) associated with unstaged cancer. The high proportion of unstaged cancer in the NZCR was noted to have led to an underestimation of the true incidence of metastatic breast cancer by 21%. Underestimation of metastatic cancer was greater for Māori (29.5%) than for NZ European (20.6%) women. Overall 5-year survival rate for unstaged cancer (NZCR) was 55.9%, which was worse than the 5-year survival rate for regional (77.3%), but better than metastatic (12.9%) disease.ConclusionsUnstaged cancer and accuracy of cancer staging in the NZCR are major sources of bias for the NZCR based research. Improving completeness and accuracy of staging data and increasing the rate of TNM cancer stage recording are identified as priorities for strengthening the usefulness of the NZCR.     

Differential cathepsin responses to inhibitor-induced feedback: E-64 and cystatin C elevate active cathepsin S and suppress active cathepsin L in breast cancer cells

Cathepsins are powerful proteases, once referred to as the lysosomal cysteine proteases, that have been implicated in breast cancer invasion and metastasis, but pharmaceutical inhibitors have suffered failures in clinical trials due to adverse side effects. Scientific advancement from lysosomotropic to cell impermeable cathepsin inhibitors have improved efficacy in treating disease, but off-target effects have still been problematic, motivating a need to better understand cellular feedback and responses to treatment with cathepsin inhibitors. To address this need, we investigated effects of E-64 and cystatin C, two broad spectrum cathepsin inhibitors, on cathepsin levels intra- and extracellularly in MDA-MB-231 breast cancer cells. Cathepsins S and L had opposing responses to both E-64 and cystatin C inhibitor treatments with paradoxically elevated amounts of active cathepsin S, but decreased amounts of active cathepsin L, as determined by multiplex cathepsin zymography. This indicated cellular feedback to selectively sustain the amounts of active cathepsin S even in the presence of inhibitors with subnanomolar inhibitory constant values. These differences were identified in cellular locations of cathepsins L and S, trafficking for secretion, co-localization with endocytosed inhibitors, and longer protein turnover time for cathepsin S compared to cathepsin L. Together, this work demonstrates that previously underappreciated cellular compensation and compartmentalization mechanisms may sustain elevated amounts of some active cathepsins while diminishing others after inhibitor treatment. This can confound predictions based solely on inhibitor kinetics, and must be better understood to effectively deploy therapies and dosing strategies that target cathepsins to prevent cancer progression.     

Assessment of lead-time bias in estimates of relative survival for breast cancer

Relative survival ratios (RSRs) can be useful for evaluating the impact of changes in cancer care on the prognosis of cancer patients or for comparing the prognosis for different subgroups of patients, but their use is problematic for cancer sites where screening has been introduced due to the potential of lead-time bias. Lead-time is survival time that is added to a patient's survival time because of an earlier diagnosis irrespective of a possibly postponed time of death. In the presence of screening it is difficult to disentangle how much of an observed improvement in survival is real and how much is due to lead-time bias. Even so, RSRs are often presented for breast cancer, a site where screening has led to early diagnosis, with the assumption that the lead-time bias is small. We describe a simulation-based framework for studying the lead-time bias due to mammography screening on RSRs of breast cancer based on a natural history model developed in a Swedish setting. We have performed simulations, using this framework, under different assumptions for screening sensitivity and breast cancer survival with the aim of estimating the lead-time bias. Screening every second year among ages 40–75 was introduced assuming that screening had no effect on survival, except for lead-time bias. Relative survival was estimated both with and without screening to enable quantification of the lead-time bias. Scenarios with low, moderate and high breast cancer survival, and low, moderate and high screening sensitivity were simulated, and the lead-time bias assessed in all scenarios.     

Oncogenic microRNA-765 promotes the growth and metastasis of breast carcinoma by directly targeting ING4

Previous investigations have proved that microRNA (miR)-765 is significantly overexpressed in multiple tumor types. Nevertheless, the underlying molecular mechanism of miR-765 in mediating breast carcinoma cell growth and metastasis remains unclear. Quantitative real-time polymerase chain reaction was used to determine the levels of miR-765 and inhibitor of growth 4 (ING4) in breast carcinoma tissues and breast carcinoma cells. Cell proliferation, colony formation, wound healing, and Transwell invasion assays were used to analysis the role of miR-765 on breast carcinoma cell growth and aggressiveness. The expressions of ING4 were determined using Western blot analysis and immunohistochemical staining. The direct target of ING4 and miR-765 was confirmed using the luciferase reporter assay. Nude mice were subcutaneously implanted with miR-765 inhibitor transfected MDA-MB-231 cells to determine the potential role of miR-765 in tumor growth in vivo. We observed that miR-765 is overexpressed in breast carcinoma tissue and breast cancer cells. By using luciferase reporter gene bioassay, we find that ING4 is the direct target of miR-765 in breast carcinoma. The level of ING4 is inversely associated with the level of miR-765. The gain-of-function and loss-of-function experiments in vitro indicate that the downregulation of miR-765 suppresses the growth, mobility, and invasion abilities of breast cancer cells by inhibiting ING4. In addition, overexpression of ING4 suppresses the aggressiveness of the MDA-BA-231 cell that is induced by miR-761 in vitro. In this study, we prove that miR-765 regulates the growth and metastasis of breast cancer via modulating miR-765-ING4-negative feedback loop.     

乳腺癌免疫组化检测在乳腺癌患者诊治中的意义分析

目的：探讨免疫组化检测在乳腺癌患者诊治中的价值。方法：随机选取2011年1月-2013年1月的68例经过空心穿刺活捡并病理确诊的乳腺癌患者为研究对象,均采用免疫组化检测ER、PR、P53、Bcl-2,全部采用CEF化疗方案治疗3个月后手术治疗,再运用免疫组化SP法检测化疗前后乳腺癌组织中以上指标的阳性表达率情况。结果：ER、PR化疗前后比较无统计学意义（P〉0．05）;而P53、Bcl-2比较有明显的差异性（P〈0．05）;ER、PR的阴性和阳性和疗效情况无明显差异性,而P53、Bcl-2的阴性和阳性表达和化疗的效果有明显的差异性,P〈0．05,具有统计学意义。结论：免疫组化检测中ER、PR对乳腺癌化疗前后无明显差异性,而化疗可通过抑制P53的表达来抑制乳腺癌增值并通过升高Bcl-2表达来调整肿瘤细胞分化。