Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation – cover

Date: 2013-02-12

Reference number: OPUSeJ 201302121734CPP

Links: to published article: 0738 http://cancerres.aacrjournals.org/content/early/2011/02/14/0008-5472.CAN-10-0738#aff-1

to pre-reviewed version: N/A

to Forum: http://www.opusej.org/library/cooperation-between-pik3ca-and-p53-mutations-in-mouse-mammary-tumor-formation-forum/

Title: Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation

Authors:  Adams,  Jessica R 1, Keli Xu1, Jeff C. Liu2, Natalia M Ruiz Agamez1, Amanda J Loch1, Ruth G Wong1, Wei Wang1, Katherine L Wright1, Timothy F Lane3, Eldad Zacksenhaus2, and Sean E Egan1,*

Abstract: PIK3CA, which codes for the p110 catalytic subunit of phosphatidylinositol 3′ kinase, is one of the most frequently mutated genes in human breast cancer. Here we describe a mouse model for PIK3CA-induced breast cancer using the ROSA26 (R26) knock-in system, where targeted Pik3ca alleles can be activated through transgenic expression of Cre recombinase. We mated Pik3caH1047R and Pik3cawt knock-in lines with MMTV-Cre transgenics, which express Cre in mammary epithelium. Starting at approximately 5 months of age, female R26-Pik3caH1047R;MMTV-Cre but not control R26-Pik3cawt;MMTV-Cre mice developed mammary tumors, as well as lymphoid and skin malignancies. R26-Pik3caH1047R;MMTV-Cre mammary tumors were typically either adenosquamous carcinoma or adenomyoepithelioma. As p53 is the most commonly mutated gene in breast cancer, we tested for genetic interaction between Pik3caH1047R and p53 loss-of-function mutations in R26-Pik3caH1047R:p53loxP/+;MMTV-Cre mice. This led to decreased survival of double mutant animals, which developed lymphoma and mammary tumors with rapid kinetics. Mammary tumors that formed in p53loxP/+;MMTV-Cre conditional mutants were either poorly differentiated adenocarcinoma or spindle cell/EMT, whereas R26-Pik3caH1047R;p53loxP/+;MMTV-Cre mammary tumors were mostly adenosquamous carcinoma or spindle cell/EMT indicating that double mutant mice develop a distinct spectrum of mammary tumors. Thus, an oncogenic variant of PIK3CA implicated in multiple human breast cancer subtypes can induce a very diverse spectrum of mammary tumors in mice. Furthermore, Pik3caH1047R shows cooperation with p53, which altered the specific tumors that formed. Thus, the two most frequently mutated genes in human breast cancer show cooperation in mammary tumor formation.

Author bio:  N/A

Sponsor editor:  N/A

 Affiliations/disclaimers/funding/acknowledgements:

1 Program in Developmental and Stem Cell Biology, The Hospital for Sick Children

2 Division of Cell & Molecular Biology, Toronto General Research Institute – University Health Network

3 OB & GYN, University of California Los Angeles

1* Corresponding Author: Sean E Egan, Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, 101 College Street, MaRS, TMDT, 14-309, Toronto, Ontario, M5G 1L7, Canada segan@sickkids.ca

Keywords:  N/A

Subject:  Science/ oncogenes

Language: English

Bibliography: see Forum

Citation:   Adams,J R et al, 2011, “Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation”, Cancer Research Published OnlineFirst February 15, 2011; doi: 10.1158/0008-5472.CAN-10-0738 http://cancerres.aacrjournals.org/content/early/2011/02/14/0008-5472.CAN-10-0738#aff-1

References: see Forum http://www.opusej.org/library/cooperation-between-pik3ca-and-p53-mutations-in-mouse-mammary-tumor-formation-forum/

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