Early stability and late random tumor progression of a HER2-positive primary breast cancer patient-derived xenograft

Lorena Landuzzi, Arianna Palladini, Claudio Ceccarelli, Sofia Asioli, Giordano Nicoletti, Veronica Giusti, Francesca Ruzzi, Marianna L Ianzano, Laura Scalambra, Roberta Laranga, Tania Balboni, Maddalena Arigoni, Martina Olivero, Raffaele A Calogero, Carla De Giovanni, Massimiliano Dall'Ora, Enrico Di Oto, Donatella Santini, Maria Pia Foschini, Maria Cristina CucchiSimone Zanotti, Mario Taffurelli, Patrizia Nanni, Pier-Luigi Lollini

Research output: Contribution to journalArticlepeer-review

Abstract

We established patient-derived xenografts (PDX) from human primary breast cancers and studied whether stability or progressive events occurred during long-term in vivo passages (up to 4 years) in severely immunodeficient mice. While most PDX showed stable biomarker expression and growth phenotype, a HER2-positive PDX (PDX-BRB4) originated a subline (out of 6 studied in parallel) that progressively acquired a significantly increased tumor growth rate, resistance to cell senescence of in vitro cultures, increased stem cell marker expression and high lung metastatic ability, along with a strong decrease of BCL2 expression. RNAseq analysis of the progressed subline showed that BCL2 was connected to three main hub genes also down-regulated (CDKN2A, STAT5A and WT1). Gene expression of progressed subline suggested a partial epithelial-to-mesenchymal transition. PDX-BRB4 with its progressed subline is a preclinical model mirroring the clinical paradox of high level-BCL2 as a good prognostic factor in breast cancer. Sequential in vivo passages of PDX-BRB4 chronically treated with trastuzumab developed progressive loss of sensitivity to trastuzumab while HER2 expression and sensitivity to the pan-HER tyrosine kinase inhibitor neratinib were maintained. Long-term PDX studies, even though demanding, can originate new preclinical models, suitable to investigate the mechanisms of breast cancer progression and new therapeutic approaches.

Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalSci. Rep.
Volume11
Issue number1
DOIs
Publication statusPublished - Jan 15 2021

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