Browsing by Subject "Triple negative breast cancer"
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Item In-depth characterization of a new patient-derived xenograft model for metaplastic breast carcinoma to identify viable biologic targets and patterns of matrix evolution within rare tumor types(Springer, 2021-08-09) Matossian, M. D.; Chang, T.; Wright, M. K.; Burks, H. E.; Elliott, S.; Sabol, R. A.; Wathieu, H.; Windsor, G. O.; Alzoubi, Madlin S.; King, C. T.; Bursavich, J. B.; Ham, A. M.; Savoie, J. J.; Nguyen, K.; Baddoo, M.; Flemington, E.; Sirenko, O.; Cromwell, E. F.; Hebert, K. L.; Lau, F.; Izadpanah, R.; Brown, H.; Sinha, S.; Zabaleta, J.; Riker, A. I.; Moroz, K.; Miele, L.; Zea, A. H.; Ochoa, A.; Bunnell, Bruce A.; Collins-Burow, B. M.; Martin, E. C.; Burow, Matthew E.Metaplastic breast carcinoma (MBC) is a rare breast cancer subtype with rapid growth, high rates of metastasis, recurrence and drug resistance, and diverse molecular and histological heterogeneity. Patient-derived xenografts (PDXs) provide a translational tool and physiologically relevant system to evaluate tumor biology of rare subtypes. Here, we provide an in-depth comprehensive characterization of a new PDX model for MBC, TU-BcX-4IC. TU-BcX-4IC is a clinically aggressive tumor exhibiting rapid growth in vivo, spontaneous metastases, and elevated levels of cell-free DNA and circulating tumor cell DNA. Relative chemosensitivity of primary cells derived from TU-BcX-4IC was performed using the National Cancer Institute (NCI) oncology drug set, crystal violet staining, and cytotoxic live/dead immunofluorescence stains in adherent and organoid culture conditions. We employed novel spheroid/organoid incubation methods (Pu.MA system) to demonstrate that TU-BcX-4IC is resistant to paclitaxel. An innovative physiologically relevant system using human adipose tissue was used to evaluate presence of cancer stem cell-like populations ex vivo. Tissue decellularization, cryogenic-scanning electron microscopy imaging and rheometry revealed consistent matrix architecture and stiffness were consistent despite serial transplantation. Matrix-associated gene pathways were essentially unchanged with serial passages, as determined by qPCR and RNA sequencing, suggesting utility of decellularized PDXs for in vitro screens. We determined type V collagen to be present throughout all serial passage of TU-BcX-4IC tumor, suggesting it is required for tumor maintenance and is a potential viable target for MBC. In this study we introduce an innovative and translational model system to study cell-matrix interactions in rare cancer types using higher passage PDX tissue.Item INHIBITION OF TRIPLE NEGATIVE AND HER-2 RESISTANT BREAST CANCER PROGRESSION BY ANNEXIN A2 ANTIBODIES(2013-04-12) Chaudhary, PankajPurpose: Herceptin, an immunotherapy directed against the Her-2 receptor, inhibits cancer growth and progression in Her-2 positive breast cancer by blocking the downstream survival pathways. In these cells however, the expression of another major tyrosine kinase receptor EGFR is significantly low. Interestingly, EGFR expression is significantly increased in Her-2 negative breast cancer thereby contributing to cancer growth and progression. Present studies were designed to investigate whether or not Annexin A2 (AnxA2), a calcium dependent phospholipid binding protein, regulated EGFR downstream signaling pathway and if the functions of EGFR can be inhibited by the AnxA2 antibody in TNBC and Herceptin resistant cancer cell lines. Methods: Triple negative breast cancer cell line MDA-MB-231 and Her-2 resistant breast cancer cell line JIMT-1 were grown in complete DMEM and DMEM/F12 medium respectively, in a humidified incubator at 37C with 5% CO2. The AnxA2 function at cell surface was blocked incubating with AnxA2 antibody (2µg/ml) after 12 h of serum starvation. The cells were treated with/without EGF (50ng/ml) for 20 min after 2 h of antibody treatment. The cell lysate was analyzed for pEGFR and EGFR mediated downstream signaling by Western blotting. Results: The results of the present study indicate that AnxA2 interacts with EGFR at the cell surface and plays an important role in the regulation of EGFR mediated downstream signaling. Treatment of MDA-MB-231 and JIMT-1 cells with AnxA2 antibody causes significant decrease in EGF-mediated phosphorylation of EGFR at Y845 and Y1068 sites. In addition, treatment of cells with AnxA2 antibody decreases the ligand induced EGFR dimerization and internalization. Our results also demonstrate that blocking cell surface AnxA2 functions causes the downregulation of proteins such as pAKT, and pERK1/2 which are regulated by EGFR resulting in lower cell survival, proliferation, and migration. Conclusions: These studies indicate that association of AnxA2 with EGFR in the membrane domain might play a positive regulatory role in keeping EGFR signaling events in an activated state in triple negative and Her-2 resistant breast cancer thus making AnxA2 an important therapeutic target.