Overall survival according to tumoral clusterin expression in breast cancer.

e11579 Background: Clusterin (CLU) is a glycoprotein expressed constitutively in many tissues and involved in various physiopathological processes. Despite CLU expression is dysregulated in many types of cancer, the specific role of CLU in tumorigenesis remains unclear. The identification of several forms of the protein, with multiple roles is an explanation for these conflicting results. Cytoplasmic CLU (cCLU) has a role in breast tumorigenesis, cancer progression and is associated with breast cancer cell lines death in vitro. However contradictory data are reported about prognostic value of cCLU on survival and clinical progression. Our objective was to estimate patient’s overall survival (OS) according to the expression of cCLU. Methods: Histological and clinical data of 158 patients diagnosed with breast cancer were retrospectively recorded. Every patients were treated in a single French university hospital between 1993 and 2001. Histological samples had been reviewed to determine hormonal status, HER2 and clusterin expression. Immunohistochemical techniques were based on standards and recommendations applied at the time of analysis. Tumors were defined as cCLU positive (cCLU +) if its expression was superior to 10%. Overall Survival rates along with standard deviations were estimated using the Kaplan-Meier method. Differences in OS according to cCLU expression were tested for significance using the log-rank test. Results: Patients had a median age of 56 years (31 – 82 years). Among the 158 patients analyzed, cCLU was overexpressed in 31 patients (19.62%). The histopathologic and clinical characteristics were not statistically different according to clusterin expression even if a trend favouring less favourable tumoural characteristics were observed in cCLU positive tumour. The median follow-up was 14.1 years (11.3 - 19.3). In univariate analysis, cCLU overexpession were not related to OS (HR = 0.86; CI95%: 0.43 - 1.70). Ten-year OS was 76% (± 4) among patients with cCLU - tumors vs 77% (± 7) in patients with cCLU + tumor (p = 0.66). Conclusions: cCLU expression does not seem to be a pronostic factor of overall survival.

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A New Risk Model Predicting Overall Survival Using Preoperative Nutritional and Inflammation Status (NIS) in Patients After Curative Resection of Colorectal Cancer

10.21203/rs.3.rs-467144/v1 ◽

2021 ◽

Author(s):

Tamuro Hayama ◽

Tsuyoshi Ozawa ◽

Mitsuo Tsukamoto ◽

Yoshihisa Fukushima ◽

Ryu Shimada ◽

...

Keyword(s):

Overall Survival ◽

Cancer Progression ◽

Curative Resection ◽

Risk Model ◽

Prognostic Score ◽

Glasgow Prognostic Score ◽

University Hospital ◽

Rank Test ◽

Preoperative Body Mass Index ◽

Neutrophil Lymphocyte Ratio

Abstract It has been shown that nutritional status correlates with survival in patients with various kinds of cancers. Besides, cancer causes inflammation which has been suggested to stimulate cancer progression. Therefore, inflammation status also has shown to reflect prognosis of cancers. In this study, we evaluated several kinds of nutritional and inflammation parameters in preoperative blood samples and constructed new risk model predicting a survival in patients with CRC (colorectal cancers). We retrospectively examined 286 patients with stage I-III CRC who had undergone curative resection in Teikyo University Hospital between 2013 to 2017. The association between overall survival (OS) and preoperative body mass index, albumin (Alb), cholesterol (Chol), and lymphocyte count, white blood cell count (WBC), neutrophil count (Neu), platelet count (Plt), C-reactive protein (CRP) were examined using Kaplan-Meier curve and log rank test. and eventually Alb, Chol, Neu, Plt, and CRP were shown to correlate with OS. Alb, Chol, Neu, Plt, and CRP were shown to correlate with OS. We constructed a new risk model (NIS: nutrition inflammation status) using these factors, and compared its usefulness with known models such as CRP-albumin ratio (CAR), Glasgow prognostic score (GPS), prognostic nutritional index (PNI), and neutrophil lymphocyte ratio (NLR). NIS prepared using nutritional indicators and inflammatory findings was useful as a new model for predicting overall survival in patients undergoing curative resection for CRC, compared with known models.

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Interaction between GRP78 and IGFBP-3 Affects Tumourigenesis and Prognosis in Breast Cancer Patients

Cancers ◽

10.3390/cancers12123821 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3821

Author(s):

Hanna A. Zielinska ◽

Carl S. Daly ◽

Ahmad Alghamdi ◽

Amit Bahl ◽

Muhammed Sohail ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Cancer Progression ◽

Survival Rates ◽

Breast Cancer Cell Lines ◽

Breast Cancer Patients ◽

Kaplan Meier ◽

Induced Apoptosis ◽

Igfbp 3

Insulin-like growth factor binding protein 3 (IGFBP-3) plays a key role in breast cancer progression and was recently shown to bind to the chaperone protein glucose-regulated protein 78 (GRP78); however, the clinical significance of this association remains poorly investigated. Here we report a direct correlation between the expression of GRP78 and IGFBP-3 in breast cancer cell lines and tumour sections. Kaplan–Meier survival plots revealed that patients with low GRP78 expression that are positive for IGFBP-3 had poorer survival rates than those with low IGFBP-3 levels, and we observed a similar trend in the publicly available METABRIC gene expression database. With breast cancer cells, in vitro IGFBP-3 enhanced induced apoptosis, however when GRP78 expression was silenced the actions of IGFBP-3 were switched from increasing to inhibiting ceramide (C2)-induced cell death and promoted cell invasion. Using immunofluorescence and cell surface biotinylation, we showed that knock-down of GRP78 negated the entry of IGFBP-3 into the cells. Together, our clinical and experimental results suggest that loss of GRP78 reduces IGFBP-3 entry into cells switching its actions to promote tumorigenesis and predicts a poor prognosis in breast cancer patients.

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MicroRNA-374b inhibits breast cancer progression through regulating CCND1 and TGFA genes

Carcinogenesis ◽

10.1093/carcin/bgab005 ◽

2021 ◽

Author(s):

Yan Liu ◽

Ai Zhang ◽

Ping-Ping Bao ◽

Li Lin ◽

Yina Wang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Molecular Mechanisms ◽

Breast Cancer Progression ◽

Breast Cancer Cell Lines ◽

Malignant Behavior

Abstract Emerging evidence indicates that microRNAs (miRNAs) play a critical role in breast cancer development. We recently reported that a higher expression of miR-374b in tumor tissues was associated with a better disease-free survival of triple-negative breast cancer (TNBC). However, the functional significance and molecular mechanisms underlying the role of miR-374b in breast cancer are largely unknown. In this current study, we evaluated the biological functions and potential mechanisms of miR-374b in both TNBC and non-TNBC. We found that miR-374b was significantly downregulated in breast cancer tissues, compared to adjacent tissues. MiR-374b levels were also lower in breast cancer cell lines, as compared to breast epithelial cells. In vitro and in vivo studies demonstrated that miR-374b modulates the malignant behavior of breast cancer cells, such as cell proliferation in 2D and 3D, cell invasion ability, colony forming ability, and tumor growth in mice. By using bioinformatics tools, we predicted that miR-374b plays a role in breast cancer cells through negatively regulating cyclin D1 (CCND1) and transforming growth factor alpha (TGFA). We further confirmed that CCND1 and TGFA contribute to the malignant behavior of breast cancer cells in vitro and in vivo. Our rescue experiments showed that overexpressing CCND1 or TGFA reverses the phenotypes caused by miR-374b overexpression. Taken together, our studies suggest that miR-374b modulates malignant behavior of breast cancer cells by negatively regulating CCND1 and TGFA genes. The newly identified miR-374b-mediated CCND1 and TGFA gene silencing may facilitate a better understanding of the molecular mechanisms of breast cancer progression.

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Clusterin Expression and Univariate Analysis of Overall Survival in Human Breast Cancer

Technology in Cancer Research & Treatment ◽

10.1177/153303460600500604 ◽

2006 ◽

Vol 5 (6) ◽

pp. 573-578 ◽

Cited By ~ 16

Author(s):

Shiwu Zhang ◽

Danfang Zhang ◽

Yue Zhu ◽

Hua Guo ◽

Xiulan Zhao ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Human Breast Cancer ◽

Univariate Analysis ◽

Human Breast ◽

Clusterin Expression

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ANTITUMOR EFFECT OF SUNITINIB AND BORTEZOMIB ON BREAST CANCER CELL LINE IN VITRO

Problems in oncology ◽

10.37469/0507-3758-2017-63-1-141-145 ◽

2017 ◽

Vol 63 (1) ◽

pp. 141-145

Author(s):

Yuliya Khochenkova ◽

Eliso Solomko ◽

Oksana Ryabaya ◽

Yevgeniya Stepanova ◽

Dmitriy Khochenkov

Keyword(s):

Breast Cancer ◽

Cell Line ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Antitumor Effect ◽

Cancer Cell Lines ◽

Breast Cancer Cell Lines ◽

Actual Problem

The discovery for effective combinations of anticancer drugs for treatment for breast cancer is the actual problem in the experimental chemotherapy. In this paper we conducted a study of antitumor effect of the combination of sunitinib and bortezomib against MDA-MB-231 and SKBR-3 breast cancer cell lines in vitro. We found that bortezomib in non-toxic concentrations can potentiate the antitumor activity of sunitinib. MDA-MB-231 cell line has showed great sensitivity to the combination of bortezomib and sunitinib in vitro. Bortezomib and sunitinib caused reduced expression of receptor tyrosine kinases VEGFR1, VEGFR2, PDGFRa, PDGFRß and c-Kit on HER2- and HER2+ breast cancer cell lines

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Small Molecular Leads Differentially Active Against HER2 Positive and Triple Negative Breast Cancer Cell Lines

Medicinal Chemistry ◽

10.2174/1573406414666181106143912 ◽

2019 ◽

Vol 15 (7) ◽

pp. 738-742 ◽

Cited By ~ 1

Author(s):

Adnan Badran ◽

Atia-tul-Wahab ◽

Sharmeen Fayyaz ◽

Elias Baydoun ◽

Muhammad Iqbal Choudhary

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Triple Negative ◽

Cancer Cell Lines ◽

Breast Cancer Cell Lines ◽

Cancer Type

Background:Breast cancer is the most prevalent cancer type in women globally. It is characterized by distinct subtypes depending on different gene expression patterns. Oncogene HER2 is expressed on the surface of cell and is responsible for cell growth regulation. Increase in HER2 receptor protein due to gene amplification, results in aggressive growth, and high metastasis in cancer cells.Methods:The current study evaluates and compares the anti-breast cancer effect of commercially available compounds against HER2 overexpressing BT-474, and triple negative MDA-MB-231 breast cancer cell lines.Results:Preliminary in vitro cell viability assays on these cell lines identified 6 lead molecules active against breast cancer. Convallatoxin (4), a steroidal lactone glycoside, showed the most potent activity with IC50 values of 0.63 ± 0.56, and 0.69 ± 0.59 µM against BT-474 and MDA-MB-231, respectively, whereas 4-[4-(Trifluoromethyl)-phenoxy] phenol (3) a phenol derivative, and Reserpine (5) an indole alkaloid selectively inhibited the growth of BT-474, and MDA-MB-231 breast cancer cells, respectively.Conclusion:These results exhibited the potential of small molecules in the treatment of HER2 amplified and triple negative breast cancers in vitro.

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Design, Synthesis, In vitro Cytotoxic Activity Evaluation, and Study of Apoptosis Inducing Effect of New Styrylimidazo[1,2-a]Pyridines as Potent Anti-Breast Cancer Agents

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180903100835 ◽

2019 ◽

Vol 19 (2) ◽

pp. 265-275 ◽

Cited By ~ 2

Author(s):

Faeze Khalili ◽

Sara Akrami ◽

Malihe Safavi ◽

Maryam Mohammadi-Khanaposhtani ◽

Mina Saeedi ◽

...

Keyword(s):

Breast Cancer ◽

Cytotoxic Activity ◽

High Yield ◽

Breast Cancer Cell Lines ◽

Pyridine Derivatives ◽

One Pot ◽

Standard Drug ◽

Three Component Reaction ◽

Anti Cancer

Background: This paper reports synthesis, cytotoxic activity, and apoptosis inducing effect of a novel series of styrylimidazo[1,2-a]pyridine derivatives. Objective: In this study, anti-cancer activity of novel styrylimidazo[1,2-a]pyridines was evaluated. Methods: Styrylimidazo[1,2-a]pyridine derivatives 4a-o were synthesized through a one-pot three-component reaction of 2-aminopyridines, cinnamaldehydes, and isocyanides in high yield. All synthesized compounds 4a-o were evaluated against breast cancer cell lines including MDA-MB-231, MCF-7, and T-47D using MTT assay. Apoptosis was evaluated by acridine orange/ethidium bromide staining, cell cycle analysis, and TUNEL assay as the mechanism of cell death. Results: Most of the synthesized compounds exhibited more potent cytotoxicity than standard drug, etoposide. Induction of apoptosis by the most cytotoxic compounds 4f, 4g, 4j, 4n, and 4m was confirmed through mentioned methods. Conclusion: In conclusion, these results confirmed the potency of styrylimidazo[1,2-a]pyridines for further drug discovery developments in the field of anti-cancer agents.

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LPTO-06. A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.029 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i7-i7

Author(s):

Jiaojiao Deng ◽

Sophia Chernikova ◽

Wolf-Nicolas Fischer ◽

Kerry Koller ◽

Bernd Jandeleit ◽

...

Keyword(s):

Breast Cancer ◽

Brain Tumors ◽

Cell Lines ◽

Chemotherapeutic Agent ◽

Leptomeningeal Metastasis ◽

Breast Cancer Cell Lines ◽

Normal Brain ◽

Breast Cancers

Abstract Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). The compound is active in suppressing the growth of GBM tumor cell lines implanted into the brain. Radiolabel distribution studies have shown significant tumor accumulation in intracranial brain tumors while sparing the adjacent normal brain tissue. Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106 photons/sec, mice were dosed i.p. twice a week with either 4 or 8 mg/kg for nine weeks. Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43

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CX-5461 Enhances the Efficacy of APR-246 via Induction of DNA Damage and Replication Stress in Triple-Negative Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22115782 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5782

Author(s):

Ashwini Makhale ◽

Devathri Nanayakkara ◽

Prahlad Raninga ◽

Kum Kum Khanna ◽

Murugan Kalimutho

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Triple Negative Breast Cancer ◽

Combination Treatment ◽

Triple Negative ◽

Annexin V ◽

Replication Stress ◽

Breast Cancer Cell Lines ◽

Combination Strategy

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking targeted therapy. Here, we evaluated the anti-cancer activity of APR-246, a P53 activator, and CX-5461, a RNA polymerase I inhibitor, in the treatment of TNBC cells. We tested the efficacy of individual and combination therapy of CX-5461 and APR-246 in vitro, using a panel of breast cancer cell lines. Using publicly available breast cancer datasets, we found that components of RNA Pol I are predominately upregulated in basal-like breast cancer, compared to other subtypes, and this upregulation is associated with poor overall and relapse-free survival. Notably, we found that the treatment of breast cancer cells lines with CX-5461 significantly hampered cell proliferation and synergistically enhanced the efficacy of APR-246. The combination treatment significantly induced apoptosis that is associated with cleaved PARP and Caspase 3 along with Annexin V positivity. Likewise, we also found that combination treatment significantly induced DNA damage and replication stress in these cells. Our data provide a novel combination strategy by utilizing APR-246 in combination CX-5461 in killing TNBC cells that can be further developed into more effective therapy in TNBC therapeutic armamentarium.

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Down-Regulation of the Proteoglycan Decorin Fills in the Tumor-Promoting Phenotype of Ionizing Radiation-Induced Senescent Human Breast Stromal Fibroblasts

Cancers ◽

10.3390/cancers13081987 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1987

Author(s):

Eleni Mavrogonatou ◽

Adamantia Papadopoulou ◽

Asimina Fotopoulou ◽

Stathis Tsimelis ◽

Heba Bassiony ◽

...

Keyword(s):

Breast Cancer ◽

Ionizing Radiation ◽

Cancer Progression ◽

Breast Cancer Cell Lines ◽

Phenotypic Trait ◽

Mrna Levels ◽

Human Breast ◽

Down Regulation ◽

Stromal Fibroblasts ◽

Poor Prognostic Factor

Down-regulation of the small leucine-rich proteoglycan decorin in the stroma is considered a poor prognostic factor for breast cancer progression. Ionizing radiation, an established treatment for breast cancer, provokes the premature senescence of the adjacent to the tumor stromal fibroblasts. Here, we showed that senescent human breast stromal fibroblasts are characterized by the down-regulation of decorin at the mRNA and protein level, as well as by its decreased deposition in the pericellular extracellular matrix in vitro. Senescence-associated decorin down-regulation is a long-lasting process rather than an immediate response to γ-irradiation. Growth factors were demonstrated to participate in an autocrine manner in decorin down-regulation, with bFGF and VEGF being the critical mediators of the phenomenon. Autophagy inhibition by chloroquine reduced decorin mRNA levels, while autophagy activation using the mTOR inhibitor rapamycin enhanced decorin transcription. Interestingly, the secretome from a series of both untreated and irradiated human breast cancer cell lines with different molecular profiles inhibited decorin expression in young and senescent stromal fibroblasts, which was annulled by SU5402, a bFGF and VEGF inhibitor. The novel phenotypic trait of senescent human breast stromal fibroblasts revealed here is added to their already described cancer-promoting role via the formation of a tumor-permissive environment.

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