Abstract
BackgroundTriple-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.MethodsWe 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.ResultsTU-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.ConclusionsHere we introduce a new TNBC PDX model and demonstrate the differences in evaluating drug sensitivity in adherent cells compared to mammosphere, or suspension, culture.
Highlights
Triple-negative breast cancer (TNBC) represents an aggressive subtype with limited therapeutic options
TU-BcX-2 K1 exhibited consistent tumor growth in each passage, taking approximately 40 days in each passage to reach minimum measurable volume (1000mm3). This was a shorter time between passages compared to another Patient-derived xenografts (PDXs) model established at the same time, TU-BcX-2O0 (Fig. 1c)
TU-BcX-2O0 is a claudin-low TNBC, treatment naïve PDX model that was established from an African-American patient
Summary
Triple-negative breast cancer (TNBC) represents an aggressive subtype with limited therapeutic options. Only 33.2% of drugs that entered phase III trials are approved for clinical use and over 90% of phase 3 clinical trials in oncology fail to meet their primary endpoints. These high failure rates highlight the need for better predictive preclinical models [3]. Triple negative breast cancer (TNBC) is a clinically aggressive, molecularly heterogeneous group of malignancies that currently has no clinically approved small molecule targeted therapies. While no preclinical model can definitively predict responses to cancer therapeutics, patient-derived xenograft (PDX) models recapitulate many of the complex components of the patient tumors and are emerging as important preclinical tools in therapeutic discovery
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