Abstract
Background: Triple-negative breast cancer (TNBC) represents an aggressive subtype with limited therapeutic options. Experimental preclinical models that recapitulate their tumors of origin can accelerate target identification, thereby potentially improving therapeutic efficacy. Patient-derived xenografts (PDXs), due to their genomic and transcriptomic fidelity to the tumors from which they are derived, are poised to improve the preclinical testing of drug-target combinations in translational models. Despite the previous development of breast and TNBC PDX models, those derived from patients with demonstrated health-disparities are lacking. Methods: We use an aggressive TNBC PDX model propagated in SCID/Beige mice that was established from an African-American woman, TU-BcX-2 K1, and assess its metastatic potential and drug sensitivities under distinct in vitro conditions. Cellular derivatives of the primary tumor or the PDX were grown in 2D culture conditions or grown in mammospheres 3D culture. Flow cytometry and fluorescence staining was used to quantify cancer stem cell-like populations. qRT-PCR was used to describe the mesenchymal gene signature of the tumor. The sensitivity of TU-BcX-2 K1-derived cells to anti-neoplastic oncology drugs was compared in adherent cells and mammospheres. Drug response was evaluated using a live/dead staining kit and crystal violet staining. Results: TU-BcX-2 K1 has a low propensity for metastasis, reflects a mesenchymal state, and contains a large burden of cancer stem cells. We show that TU-BcX-2 K1 cells have differential responses to cytotoxic and targeted therapies in 2D compared to 3D culture conditions insofar as several drug classes conferred sensitivity in 2D but not in 3D culture, or cells grown as mammospheres. Conclusions: Here we introduce a new TNBC PDX model and demonstrate the differences in evaluating drug sensitivity in adherent cells compared to mammosphere, or suspension, culture.
| Original language | English (US) |
|---|---|
| Article number | 205 |
| Journal | BMC cancer |
| Volume | 19 |
| Issue number | 1 |
| DOIs | |
| State | Published - Mar 7 2019 |
Funding
This work was supported by grants from National Institute of Health (NIH) (Grants No. R01-CA174785-A1 (BC-B) and R01CA125806–02 (MEB)). Additionally, this work was also supported in part by 1 U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health, which funds the Louisiana Clinical and Translational Science Center (LA-CATS; BAB). The grants provided by NIH were necessary for purchase of the equipment and materials, and personnel required to perform the experiments for data described in this study. The LA-CATS grant supported and provided materials and equipment that were necessary to obtain and establish the patient-derived xenograft tumor tissue utilized in this study. BMC-B, MEB and BAB, recipients of the grants, also were integral in data interpretation, revising the manuscript, and approving the final version. This work was also supported in part by the Biospecimen Core Laboratory of the Louisiana Cancer Research Consortium. From the LCRC Core we would especially like to acknowledge Alex Alfortish whom played an integral role in coordination and acquisition of TNBC tissue specimen. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We are also grateful to Sharon Miller for her assistance in coordinating and obtaining the PDX tissue at the time of surgeries. We are also appreciative of Krewe de Pink for their support in this project. Importantly, we would also like to thank the patients who consent to donate their tissue to benefit breast cancer research.
Keywords
- Chemoresistance
- Mammosphere
- Patient-derived xenograft
- Triple-negative breast cancer
ASJC Scopus subject areas
- Oncology
- Genetics
- Cancer Research
