Abstract
IntroductionPerp 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.MethodsImmunofluorescence 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/+;p53fl/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.ResultsWe 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.ConclusionsTogether, 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.
Highlights
p53 apoptosis effector related to PMP-22 (Perp) is a transcriptional target of both p53 during DNA damage-induced apoptosis and p63 during stratified epithelial development
We show that Perp protein is expressed in the mammary epithelium, where it colocalizes with desmosomes
Perp is expressed in the mammary epithelium To decipher the function of Perp and desmosomes in the integrity and function of the mammary epithelium, we first examined the localization of Perp in wild-type 14-week-old virgin female mouse mammary glands
Summary
Perp is a transcriptional target of both p53 during DNA damage-induced apoptosis and p63 during stratified epithelial development. Proper regulation of the processes controlling mammary epithelial form and function is critical, as its dysregulation can impair the normal architecture or behavior of the mammary epithelium, leading to cancer development [1]. Adherens junctions promote the cell-cell adhesion required for organizing epithelial cells into sheets and are fundamental for allowing dynamic rearrangements of epithelia necessary for maintaining homeostasis. Adherens junctions are important for normal tissue development, function, and organization [3,4,5,6]. Cell-culture experiments have suggested a role for desmosomal cadherinmediated adhesion in some aspects of mammary epithelial morphogenesis and organization [9], but desmosome function in the mammary gland has not been examined in vivo
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