Abstract
ABSTRACTUnderstanding the mechanisms of cancer therapeutic resistance is fundamental to improving cancer care. There is clear benefit from chemotherapy in different breast cancer settings; however, knowledge of the mutations and genes that mediate resistance is incomplete. In this study, by modeling chemoresistance in patient-derived xenografts (PDXs), we show that adaptation to therapy is genetically complex and identify that loss of transcription factor 4 (TCF4; also known as ITF2) is associated with this process. A triple-negative BRCA1-mutated PDX was used to study the genetics of chemoresistance. The PDX was treated in parallel with four chemotherapies for five iterative cycles. Exome sequencing identified few genes with de novo or enriched mutations in common among the different therapies, whereas many common depleted mutations/genes were observed. Analysis of somatic mutations from The Cancer Genome Atlas (TCGA) supported the prognostic relevance of the identified genes. A mutation in TCF4 was found de novo in all treatments, and analysis of drug sensitivity profiles across cancer cell lines supported the link to chemoresistance. Loss of TCF4 conferred chemoresistance in breast cancer cell models, possibly by altering cell cycle regulation. Targeted sequencing in chemoresistant tumors identified an intronic variant of TCF4 that may represent an expression quantitative trait locus associated with relapse outcome in TCGA. Immunohistochemical studies suggest a common loss of nuclear TCF4 expression post-chemotherapy. Together, these results from tumor xenograft modeling depict a link between altered TCF4 expression and breast cancer chemoresistance.
Highlights
Triple-negative breast cancer (TNBC), defined by the absence of the estrogen and progesterone receptors (ER and PR, respectively) and of human epidermal growth factor receptor 2 (HER2), accounts for 15-20% of all breast cancer cases (Foulkes et al, 2010)
The patientderived xenografts (PDXs) was established for three passages before chemoresistance modeling was initiated
Replicates of the PDX were treated in parallel with cisplatin, fluorouracil, lurbinectedin or olaparib
Summary
Triple-negative breast cancer (TNBC), defined by the absence (or relative low expression) of the estrogen and progesterone receptors (ER and PR, respectively) and of human epidermal growth factor receptor 2 (HER2), accounts for 15-20% of all breast cancer cases (Foulkes et al, 2010). Conventional chemotherapy – CMF (cyclophosphamide, methotrexate and fluorouracil) and/or anthracycline- and taxane-containing regimens – is the basis of TNBC treatment according to the majority of national and international guidelines (Coates et al, 2015) These therapies typically give response rates of 30-70%, but they are often not durable, with a time to progression of 6-10 months (von Minckwitz et al, 2012). Given the clinical impact of therapeutic resistance, there is renewed interest in platinum-based drugs, either as a single agent or in combination therapy This interest is principally led by the high frequency of germline and/or somatic alterations in the BRCA1 gene in TNBC tumors (Silver et al, 2010). PDX-based modeling of breast cancer chemoresistance leads
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