Evaluation of deacetylase inhibition in metaplastic breast carcinoma using multiple derivations of preclinical models of a new patient-derived tumor

• Published in: PloS one 2020-10, Vol.15 (10), p.e0226464
• Main Authors: Chang, Tiffany C, Matossian, Margarite D, Elliott, Steven, Burks, Hope E, Sabol, Rachel A, Ucar, Deniz A, Wathieu, Henri, Zabaleta, Jovanny, Del Valle, Luis, Gill, Sukhmani, Martin, Elizabeth, Riker, Adam I, Miele, Lucio, Bunnell, Bruce A, Burow, Matthew E, Collins-Burow, Bridgette M
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biology and Life Sciences; Breast cancer; Breast carcinoma; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cancer therapies; Care and treatment; Cell cycle; Cell Cycle Proteins - genetics; Cell Line, Tumor; Cell migration; Cell morphology; Cell Movement - drug effects; Cell Survival - drug effects; Chemotherapy; Clinical trials; Colorectal cancer; Cytology; Depsipeptides - administration & dosage; Depsipeptides - pharmacology; Diagnosis; Drug Synergism; Epithelial-Mesenchymal Transition - drug effects; Evaluation; Explants; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genes; Growth rate; Hematology; Heterogeneity; Histone deacetylase; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - pharmacology; Humans; Inhibitors; Kidney cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - secondary; Lymphoma; Medicine; Medicine and Health Sciences; Mesenchyme; Metastases; Metastasis; Mice; Middle Aged; Morphology; Mutation; Neoplastic Cells, Circulating - drug effects; Oncology; Organoids; Panobinostat - administration & dosage; Panobinostat - pharmacology; Patient-Specific Modeling; Patients; Pharmacology; Phenotypes; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Surgical implants; Synergistic effect; Testing; Tumor cells; Tumors; Xenografts; Xenotransplantation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0226464

Metaplastic breast carcinoma (MBC) is a clinically aggressive and rare subtype of breast cancer, with similar features to basal-like breast cancers. Due to rapid growth rates and characteristic heterogeneity, MBC is often unresponsive to standard chemotherapies; and novel targeted therapeutic discovery is urgently needed. Histone deacetylase inhibitors (DACi) suppress tumor growth and metastasis through regulation of the epithelial-to-mesenchymal transition axis in various cancers, including basal-like breast cancers. We utilized a new MBC patient-derived xenograft (PDX) to examine the effect of DACi therapy on MBC. Cell morphology, cell cycle-associated gene expressions, transwell migration, and metastasis were evaluated in patient-derived cells and tumors after treatment with romidepsin and panobinostat. Derivations of our PDX model, including cells, spheres, organoids, explants, and in vivo implanted tumors were treated. Finally, we tested the effects of combining DACi with approved chemotherapeutics on relative cell biomass. DACi significantly suppressed the total number of lung metastasis in vivo using our PDX model, suggesting a role for DACi in preventing circulating tumor cells from seeding distal tissue sites. These data were supported by our findings that DACi reduced cell migration, populations, and expression of mesenchymal-associated genes. While DACi treatment did affect cell cycle-regulating genes in vitro, tumor growth was not affected compared to controls. Importantly, gene expression results varied depending on the cellular or tumor system used, emphasizing the importance of using multiple derivations of cancer models in preclinical therapeutic discovery research. Furthermore, DACi sensitized and produced a synergistic effect with approved oncology therapeutics on inherently resistant MBC. This study introduced a role for DACi in suppressing the migratory and mesenchymal phenotype of MBC cells through regulation of the epithelial-mesenchymal transition axis and suppression of the CTC population. Preliminary evidence that DACi treatment in combination with MEK1/2 inhibitors exerts a synergistic effect on MBC cells was also demonstrated.