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A novel patient-derived xenograft model for claudin-low triple-negative breast cancer.

ABSTRACT: BACKGROUND:Triple-negative breast cancer (TNBC) subtypes are clinically aggressive and cannot be treated with targeted therapeutics commonly used in other breast cancer subtypes. The claudin-low (CL) molecular subtype of TNBC has high rates of metastases, chemoresistance and recurrence. There exists an urgent need to identify novel therapeutic targets in TNBC; however, existing models utilized in target discovery research are limited. Patient-derived xenograft (PDX) models have emerged as superior models for target discovery experiments because they recapitulate features of patient tumors that are limited by cell-line derived xenograft methods. METHODS:We utilize immunohistochemistry, qRT-PCR and Western Blot to visualize tumor architecture, cellular composition, genomic and protein expressions of a new CL-TNBC PDX model (TU-BcX-2O0). We utilize tissue decellularization techniques to examine extracellular matrix composition of TU-BcX-2O0. RESULTS:Our laboratory successfully established a TNBC PDX tumor, TU-BCX-2O0, which represents a CL-TNBC subtype and maintains this phenotype throughout subsequent passaging. We dissected TU-BCx-2O0 to examine aspects of this complex tumor that can be targeted by developing therapeutics, including the whole and intact breast tumor, specific cell populations within the tumor, and the extracellular matrix. CONCLUSIONS:Here, we characterize a claudin-low TNBC patient-derived xenograft model that can be utilized for therapeutic research studies.

SUBMITTER: Matossian MD

PROVIDER: S-EPMC5948145 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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A novel patient-derived xenograft model for claudin-low triple-negative breast cancer.

Matossian Margarite D MD Burks Hope E HE Bowles Annie C AC Elliott Steven S Hoang Van T VT Sabol Rachel A RA Pashos Nicholas C NC O'Donnell Benjamen B Miller Kristin S KS Wahba Bahia M BM Bunnell Bruce A BA Moroz Krzysztof K Zea Arnold H AH Jones Steven D SD Ochoa Augusto C AC Al-Khami Amir A AA Hossain Fokhrul F Riker Adam I AI Rhodes Lyndsay V LV Martin Elizabeth C EC Miele Lucio L Burow Matthew E ME Collins-Burow Bridgette M BM

Breast cancer research and treatment 20180201 2

<h4>Background</h4>Triple-negative breast cancer (TNBC) subtypes are clinically aggressive and cannot be treated with targeted therapeutics commonly used in other breast cancer subtypes. The claudin-low (CL) molecular subtype of TNBC has high rates of metastases, chemoresistance and recurrence. There exists an urgent need to identify novel therapeutic targets in TNBC; however, existing models utilized in target discovery research are limited. Patient-derived xenograft (PDX) models have emerged a ...[more]

PMID: 29392581

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Project description:Extensive efforts, through cell line-based models, have been made to characterize the androgen receptor (AR) signaling pathway in triple-negative breast cancer (TNBC). However, these efforts have not yet reached a consensus with regards to the mechanism of AR in TNBC. Considering that patient-derived xenografts (PDXs) are more appropriate than cell line-based models for recapitulating the structural and molecular features of a patient's tumor, we have identified and molecularly characterized two new AR-positive TNBC PDX models and assessed the impacts of AR agonist [dihydrotestosterone (DHT)] and antagonist (enzalutamide) on tumor growth and gene expression profiles by utilizing immunohistochemistry, western blots, and RNA-Seq analyses. Two PDX models, termed TN1 and TN2, were derived from two grade-3 TNBC tumors, each harboring 1∼5% of AR nuclear positive cancer cells. DHT activated AR in both PDX tumors by increasing nuclear localization and AR protein levels. However, the endpoint tumor volume of DHT-treated TN1 was 3-folds smaller than that of non-treated TN1 tumors. Conversely, the endpoint tumor volume of DHT-treated TN2 was 2-folds larger than that of non-treated TN2. Moreover, enzalutamide failed to antagonize DHT-induced tumor growth in TN2. The RNA-Seq analyses revealed that DHT mainly suppressed gene expression in TN1 (961 down-regulated genes versus 149 up-regulated genes), while DHT promoted gene expression in TN2 (673 up-regulated genes versus 192 down-regulated genes). RNA-Seq data predicted distinct TNBC molecular subtypes for TN1 and TN2. TN1 correlated to a basal-like 1 (BL1) subtype, and TN2 correlated to a basal-like 2 (BL2) subtype. These analyses suggest that TN1 and TN2, which both express functional AR, are two molecularly distinct PDX models. The molecular characterization of these PDX models expands our current knowledge on AR-positive TNBC. Our results do not support that AR is a suitable therapeutic target in TNBC. To our best knowledge, the molecular mechanisms of AR in TNBC are equivocal and should be evaluated using clinically relevant models, considering both the heterogeneous expression of AR in TNBC and the general complexities of AR signaling.

Dataset Information

A novel patient-derived xenograft model for claudin-low triple-negative breast cancer.

Publications

A novel patient-derived xenograft model for claudin-low triple-negative breast cancer.

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