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Joseph T Decker, Eric C Hobson, Yining Zhang, Seungjin Shin, Alexandra L Thomas, Jacqueline S Jeruss, Kelly B Arnold, Lonnie D Shea
The development of resistance to targeted therapeutics is a challenging issue for the treatment of cancer. Cancers that have mutations in BRCA, a DNA repair protein, have been treated with poly (ADP-ribose) polymerase (PARP) inhibitors, which target a second DNA repair mechanism with the aim of inducing synthetic lethality. While these inhibitors have shown promise clinically, the development of resistance can limit their effectiveness as a therapy. This study investigated mechanisms of resistance in BRCA-mutated cancer cells (HCC1937) to Olaparib (AZD2281) using TRACER, a technique for measuring dynamics of transcription factor (TF) activity in living cells...
March 21, 2017: Biotechnology and Bioengineering
Rakesh Sathish Nair, Manoj Easwaran Potti, Ratheeshkumar Thankappan, Sivakumar Krishnankutty Chandrika, M R Prathapachandra Kurup, Priya Srinivas
Novel chelated metal complexes were synthesized from carbohydrazones to thiocarbohydrazones using metal-based drug designing platforms and their combination effect with Pb, a naphthaquinone were analyzed for anticancer activity in breast cancer cell lines. A panel of BRCA1 wild-type and mutated breast cancer cells: MCF-7 (BRCA1(+) /ER(+) ), MDA-MB-231 (BRCA1(+) /ERα(-) ), HCC-1937 (BRCA1(-) /ERα(-) ), HCC1937/wt BRCA1, MX1 (BRCA1(-) /ERα(-) ), and MDA-MB-436 (BRCA1(-) /ERα(-) ) were screened for anti-cancer activity...
January 4, 2017: Molecular Carcinogenesis
Ramiro Vázquez, María E Riveiro, Lucile Astorgues-Xerri, Elodie Odore, Keyvan Rezai, Eugenio Erba, Nicolò Panini, Andrea Rinaldi, Ivo Kwee, Luca Beltrame, Mohamed Bekradda, Esteban Cvitkovic, Francesco Bertoni, Roberta Frapolli, Maurizio D'Incalci
Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subgroup of breast tumors clinically defined by the lack of estrogen, progesterone and HER2 receptors, limiting the use of the targeted therapies employed in other breast malignancies. Recent evidence indicates that c-MYC is a key driver of TNBC. The BET-bromodomain inhibitor OTX015 (MK-8628) has potent antiproliferative activity accompanied by c-MYC down-regulation in several tumor types, and has demonstrated synergism with the mTOR inhibitor everolimus in different models...
January 31, 2017: Oncotarget
Karin Kashii-Magaribuchi, Rie Takeuchi, Yuko Haisa, Akemi Sakamoto, Aimi Itoh, Yuki Izawa, Miyuki Isa, Mayu Fukuzawa, Motonobu Murakami, Rei Takahashi
We established an experimental system that can induce p53-dependent apoptosis by doxycycline treatment to analyze characteristics of the apoptosis-resistant cancer cell subpopulation in the human breast cancer cell line HCC1937. Expression patterns of the stem cell markers, ALDH1A3 and Sox-2, the luminal differentiation marker, GATA3 and the proliferation index marker, Ki-67 were analyzed using immunostaining and fluorescence-activated cell sorting (FACS). After doxycycline treatment, the number of viable cells was gradually decreased over seven days in a time-dependent manner due to p53-induced apoptosis; however, the number of smaller-sized ALDH1A3(+) cells assessed by immunostaining increased sharply after 1 day of doxycycline treatment, suggesting their apoptosis-resistant nature...
November 1, 2016: Acta Histochemica et Cytochemica
Janice García-Quiroz, Rocío García-Becerra, Nancy Santos-Martínez, Euclides Avila, Fernando Larrea, Lorenza Díaz
BACKGROUND: In normal and neoplastic cells, growth-promoting, proangiogenic, cytotoxic and pro-apoptotic effects have all been attributed to cathelicidin antimicrobial peptide (CAMP). Nevertheless, little is known about the factors regulating this peptide expression in breast cancer. Herein we asked if the well-known antineoplastic hormone calcitriol could differentially modulate CAMP gene expression in human breast cancer cells depending on the cell phenotype in terms of efficacy and potency...
November 10, 2016: Journal of Biomedical Science
Vijesh J Bhute, Yan Ma, Xiaoping Bao, Sean P Palecek
Breast tumors are characterized into subtypes based on their surface marker expression, which affects their prognosis and treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in clinical trials, both as single agents and in combination with other chemotherapeutics, in several subtypes of breast cancer patients. Here, we used NMR-based metabolomics to probe cell line-specific effects of the PARP inhibitor Veliparib and radiation on metabolism in three breast cancer cell lines...
November 4, 2016: Scientific Reports
Yan Zhou, Shuchen Lin, Kuo-Fu Tseng, Kun Han, Yaling Wang, Zhi-Hua Gan, Da-Liu Min, Hai-Yan Hu
BACKGROUND: Triple-negative breast cancer (TNBC) has aggressive progression with poor prognosis and ineffective treatments. Selumetinib is an allosteric, ATP-noncompetitive inhibitor of MEK1/2, which has benn known as effective antineoplastic drugs for several malignant tumors. We hypothesized that Selumetinib might be potential drug for TNBC and explore the mechanism. METHODS: After treated with Selumetinib, the viability and mobility of HCC1937 and MDA-MB-231 were detected by MTT, tunnel, wound-healing assay, transwell assay and FCM methods...
October 21, 2016: BMC Cancer
Hongchao Jiang, Ceshi Chen, Qiangming Sun, Jing Wu, Lijuan Qiu, Change Gao, Weiqing Liu, Jun Yang, Nie Jun, Jian Dong
BACKGROUND: Semaphorin 4D (Sema4D) is highly expressed in certain types of tumors and functions in the regulation of tumor angiogenesis and growth. However, it is still not clear regarding the roles of Sema4D in breast cancer. This study was designed to explore the effects of Sema4D on proliferation, cell cycle progression, apoptosis, invasion, migration, tumor growth, and angiogenesis in breast cancer. MATERIALS AND METHODS: The expression level of Sema4D was investigated in MCF10A, 184A1, HCC1937, MDA-MB-468, MDA-MB-231, Hs578T, BT474, MCF-7, and T47D breast cancer cell lines by Western blotting analysis...
2016: OncoTargets and Therapy
Kamila A Marzec, Estefania Martino-Echarri, Irmgard Irminger-Finger, Beric R Henderson
We previously showed that BARD1 is a shuttling protein with pro-apoptotic activity in MCF-7 breast cancer cells. BARD1 is expressed as splice variant isoforms in breast cancer. Here we characterized YFP-tagged BARD1 splice variants (beta, omega, phi, ΔRIN, epsilon) for subcellular localization and apoptotic efficacy. We found that loss of nuclear localization (NLS) or export (NES) sequences influenced cellular distribution. The beta and omega variants (+NLS/-NES) shifted exclusively to the nucleus. In contrast, BARD1-epsilon (-NLS/+NES) was mostly cytoplasmic...
October 10, 2016: Cancer Letters
Lian Chen, Hengmin Cui, Jing Fang, Huidan Deng, Ping Kuang, Hongrui Guo, Xun Wang, Ling Zhao
Glutamine provides cancer cells with the energy required to synthesize macromolecules. Methods which block glutamine metabolism in treatment of breast cancer inhibit oncogenic transformation and tumor growth. We investigated whether inhibiting glutamine metabolism produces effects that are synergistic with those produced by drugs which damage DNA in triple-negative breast cancer cells. HCC1937 and BT-549 breast cancer cells were co-treated with either cisplatin or etoposide in combination with BPTES (a specific inhibitor of glutaminase 1) or exposure to a glutamine-free medium, and the cell proliferation and cell apoptosis were measured by flow cytometry, immunoblotting studies, and CCK-8 assays...
August 23, 2016: Oncotarget
Jing Wu, Ye Ding, Chuan-Huizhi Chen, Zhongmei Zhou, Chunyong Ding, Haiying Chen, Jia Zhou, Ceshi Chen
Triple-negative breast cancer (TNBC) remains the leading cause of death among women with breast cancer worldwide. Oridonin is a natural anti-cancer compound that is isolated from the traditional Chinese herb Rabdosia rubescens. However, the antitumor efficacies of oridonin in the treatments of TNBC and other cancers are far from ideal. In this study, we investigated a series of newly designed oridonin analogs in terms of their actions against HCC1806 and HCC1937 TNBC cell lines and identified CYD-6-28, which significantly inhibits cancer cell proliferation and induces G2/M-phase cell cycle arrest and apoptosis...
October 1, 2016: Cancer Letters
Aurélia Noll, Giuditta Illuzzi, Jean-Christophe Amé, Françoise Dantzer, Valérie Schreiber
BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors have entered the clinics for their promising anticancer effect as adjuvant in chemo- and radiotherapy and as single agent on BRCA-mutated tumours. Poly(ADP-ribose) glycohydrolase (PARG) deficiency was also shown to potentiate the cytotoxicity of genotoxic agents and irradiation. The aim of this study is to investigate the effect of PARG deficiency on BRCA1- and/or PTEN-deficient tumour cells. METHODS: Since no PARG inhibitors are available for in vivo studies, PARG was depleted by siRNA in several cancer cell lines, proficient or deficient for BRCA1 and/or PTEN...
2016: Cancer Cell International
L Tang, D Wei, F Yan
Although increasing evidence has documented that microRNA-145 (miR-145) acts as a tumor suppressor in breast cancer, its exact role in triple-negative breast cancer (TNBC) remains poorly defined. In this study, the expression of miR-145 in human TNBC cells and samples from 30 patients was analyzed by stem-loop real-time PCR. We found that miR-145 was significantly downregulated in TNBC tissues and cells. Upregulating miR-145 in HCC1937 cells dramatically suppressed cell proliferation and induced G1-phase arrest, whereas MDA-MB-231 cells did not show growth inhibition...
August 2016: Cancer Gene Therapy
Yuexi Gu, Mikko Helenius, Kristiina Väänänen, Daria Bulanova, Jani Saarela, Anna Sokolenko, John Martens, Evgeny Imyanitov, Sergey Kuznetsov
Germ-line or somatic inactivation of BRCA1 is a defining feature for a portion of human breast cancers. Here we evaluated the anti-proliferative activity of 198 FDA-approved and experimental drugs against four BRCA1-mutant (HCC1937, MDA-MB-436, SUM1315MO2, and SUM149PT) and four BRCA1-wild-type (MDA-MB-231, SUM229PE, MCF10A, and MCF7) breast cancer cell lines. We found that all BRCA1-mutant cell lines were insensitive to inhibitors of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) Selumetinib and Pimasertib in contrast to BRCA1-wildtype control cell lines...
2016: Scientific Reports
Veena Somasundaram, Sreelatha K Hemalatha, Krishnendu Pal, Sutapa Sinha, Asha S Nair, Debabrata Mukhopadhyay, Priya Srinivas
BACKGROUND: Studies over the past decade and half have identified cancer stem cells (CSCs) to be responsible for tumorigenesis, invasion, sustenance of metastatic disease, radio- and chemo-resistance and tumor relapse. Recent reports have described the plasticity of breast CSCs (BCSCs) to shift between the epithelial and mesenchymal phenotypes via Epithelial-Mesenchymal Transition (EMT) and Mesenchymal-Epithelial Transition (MET) states as the reason for their invasive capabilities. Additionally, BRCA1 has been found to be a mammary stem cell fate determinant...
2016: BMC Cancer
Kathrin Halfter, Oliver Hoffmann, Nina Ditsch, Mareike Ahne, Frank Arnold, Stefan Paepke, Dieter Grab, Ingo Bauerfeind, Barbara Mayer
BACKGROUND: Targeted anti-HER2 therapy has greatly improved the prognosis for many breast cancer patients. However, treatment for HER2 negative disease is currently still selected from a multitude of untargeted chemotherapeutic treatment options. A predictive test was developed using patient-derived spheroids to identify the most effective therapy for patients with HER2 negative breast cancer of all stages, for clinically relevant subgroups, as well as individual patients. METHODS: Tumor samples from 120 HER2 negative patients obtained through biopsy or surgical excision were tested in the breast cancer spheroid model using scaffold-free cell culture...
2016: Journal of Translational Medicine
Guang Ouyang, Rongsheng Tong, Jinqi Li, Lan Bai, Liang Ouyang, Xingmei Duan, Fengqiong Li, Pin He, Jianyou Shi, Yuxin He
A series of novel 5-hydrosulfonyl-1H-benzo[d]imidazol-2(3H)-one derivatives bearing natural product substructures has been successfully synthesized and their antitumor activity studied. These newly synthesized derivatives were characterized by ¹H-NMR, (13)C-NMR and high resolution mass spectral data, then screened as antitumor agents against the A549, HCC1937, and MDA-MB-468 human tumor cell lines using MTT cell proliferation assays. The results show that some of these compounds can effectively inhibit the growth of these cancerous cells, with compound 5b being the best one (IC50 = 2...
April 20, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Adisorn Ratanaphan, Tidarat Nhukeaw, Khwanjira Hongthong, Paul J Dyson
BACKGROUND: The RAPTA-EA1 complex [ruthenium(II)-arene 1,3,5-triaza-7-phosphaadamantane (pta) complex with an arene-tethered ethacrynic acid ligand] has been reported to overcome drug resistance that developed due to the current use of platinum-based treatments. However, the exact mechanism of action of RAPTA-EA1 remains largely unexplored and unknown. OBJECTIVE: Here we have further studied the effect of RAPTA-EA1 on BRCA1-defective HCC1937 breast cancer cells and compared its effects on BRCA1-competent MCF-7 breast cancer cells...
2017: Anti-cancer Agents in Medicinal Chemistry
Elisabetta Crippa, Marco Folini, Marzia Pennati, Nadia Zaffaroni, Marco A Pierotti, Manuela Gariboldi
Expression of miR-342 has been strongly correlated with estrogen receptor (ER) status in breast cancer, where it is highest in ER-positive and lowest in triple-negative tumors. We investigated the effects of miR-342 transfection in the triple-negative breast cancer cell lines MDA-MB-231 and HCC1937, the latter carrying a germ-line BRCA1 mutation. Reconstitution of miR-342 led to caspase-dependent induction of apoptosis only in HCC1937 cells, while overexpression of wild-type BRCA1 in HCC1937 cells counteracted miR-342-mediated induction of apoptosis, suggesting that miR-342 overexpression and the lack of functional BRCA1 result in a synthetic lethal phenotype...
April 5, 2016: Oncotarget
Kaichun Li, Mingzhen Ying, Dan Feng, Yan Chen, Jingwen Wang, Yajie Wang
Triple-negative breast cancer (TNBC) is a special subtype of breast cancer, which is characterized by the negative form of estrogen receptor (ER), progesterone receptor (PR) and human epithelial growth factor receptor 2 (HER2). TNBC accounts for ~15% of all breast cancer forms, and often leads to high mortality and poor prognosis. Structural maintenance of chromosome 1 (SMC1) is a subunit of the cohesion protein complex. Brachyury is a protein that is encoded by the T gene in humans, which is a transcription factor within the T-box complex of genes...
April 2016: Oncology Reports
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