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Breast Cancer Research
Published in: Breast Cancer Research 2/2012

Open Access 01-04-2012 | Research article

Deficiency of the p53/p63 target Perp alters mammary gland homeostasis and promotes cancer

Authors: Rachel L Dusek, Jamie L Bascom, Hannes Vogel, Sylvain Baron, Alexander D Borowsky, Mina J Bissell, Laura D Attardi

Published in: Breast Cancer Research | Issue 2/2012

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Abstract

Introduction

Perp is a transcriptional target of both p53 during DNA damage-induced apoptosis and p63 during stratified epithelial development. Perp-/- mice exhibit postnatal lethality associated with dramatic blistering of the epidermis and oral mucosa, reflecting a critical role in desmosome-mediated intercellular adhesion in keratinocytes. However, the role of Perp in tissue homeostasis in other p63-dependent stratified epithelial tissues is poorly understood. Given that p63 is essential for proper mammary gland development and that cell adhesion is fundamental for ensuring the proper architecture and function of the mammary epithelium, here we investigate Perp function in the mammary gland.

Methods

Immunofluorescence and Western blot analysis were performed to characterize Perp expression and localization in the mouse mammary epithelium throughout development. The consequences of Perp deficiency for mammary epithelial development and homeostasis were examined by using in vivo mammary transplant assays. Perp protein levels in a variety of human breast cancer cell lines were compared with those in untransformed cells with Western blot analysis. The role of Perp in mouse mammary tumorigenesis was investigated by aging cohorts of K14-Cre/+;p53 fl/fl mice that were wild-type or deficient for Perp. Mammary tumor latency was analyzed, and tumor-free survival was assessed using Kaplan-Meier analysis.

Results

We show that Perp protein is expressed in the mammary epithelium, where it colocalizes with desmosomes. Interestingly, although altering desmosomes through genetic inactivation of Perp does not dramatically impair mammary gland ductal development, Perp loss affects mammary epithelial homeostasis by causing the accumulation of inflammatory cells around mature mammary epithelium. Moreover, we show reduced Perp expression in many human breast cancer cell lines compared with untransformed cells. Importantly, Perp deficiency also promotes the development of mouse mammary cancer.

Conclusions

Together, these observations demonstrate an important role for Perp in normal mammary tissue function and in mammary cancer suppression. In addition, our findings highlight the importance of desmosomes in cancer suppression and suggest the merit of evaluating Perp as a potential prognostic indicator or molecular target in breast cancer therapy.
Appendix
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Metadata
Title
Deficiency of the p53/p63 target Perp alters mammary gland homeostasis and promotes cancer
Authors
Rachel L Dusek
Jamie L Bascom
Hannes Vogel
Sylvain Baron
Alexander D Borowsky
Mina J Bissell
Laura D Attardi
Publication date
01-04-2012
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 2/2012
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr3171

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