Targeted Pten deletion plus p53-R270H mutation in mouse mammary epithelium induces aggressive claudin-low and basal-like breast cancer

Breast Cancer Research : BCR
Sharon WangEldad Zacksenhaus

Abstract

Triple-negative breast cancer (TNBC), an aggressive disease comprising several subtypes including basal-like and claudin-low, involves frequent deletions or point mutations in TP53, as well as loss of PTEN. We previously showed that combined deletion of both tumor suppressors in the mouse mammary epithelium invariably induced claudin-low-like TNBC. The effect of p53 mutation plus Pten deletion on mammary tumorigenesis and whether this combination can induce basal-like TNBC in the mouse are unknown. WAP-Cre:Pten(f/f):p53(lox.stop.lox_R270H) composite mice were generated in which Pten is deleted and a p53-R270H mutation in the DNA-binding domain is induced upon expression of Cre-recombinase in pregnancy-identified alveolar progenitors. Tumors were characterized by histology, marker analysis, transcriptional profiling [GEO-GSE75989], bioinformatics, high-throughput (HTP) FDA drug screen as well as orthotopic injection to quantify tumor-initiating cells (TICs) and tail vein injection to identify lung metastasis. Combined Pten deletion plus induction of p53-R270H mutation accelerated formation of four distinct mammary tumors including poorly differentiated adenocarcinoma (PDA) and spindle/mesenchymal-like lesions. Transplantation as...Continue Reading

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Citations

Aug 30, 2016·The Journal of Clinical Investigation·Robert A JonesEldad Zacksenhaus
Mar 30, 2017·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Ebubekir Dirican, Mustafa Akkiprik
Sep 21, 2019·Physiological Reviews·Nai Yang FuJane E Visvader
Dec 29, 2019·Breast Cancer Research : BCR·Wenlin YuanSomasekar Seshagiri
Dec 15, 2019·Scientific Reports·Dong-Yu WangEldad Zacksenhaus
Nov 8, 2020·Carcinogenesis·Yan SteinVarda Rotter

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Datasets Mentioned

BETA
GSE75989
GSE18229
GSE3165

Methods Mentioned

BETA
genotyping
PCR
biopsies
xenografts

Software Mentioned

Enrichment Map
limma
Partek
TreeView
GSEA
Cytoscape
R
HTP
GSEA )
Java

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