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

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

doi:10.1186/bcr3171

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

Journal Article · Fri Apr 20 00:00:00 EDT 2012 · Breast Cancer Research

DOI:https://doi.org/10.1186/bcr3171· OSTI ID:1626698

Dusek, Rachel L. ^[1]; Bascom, Jamie L. ^[2]; Vogel, Hannes ^[3]; Baron, Sylvain ^[3]; Borowsky, Alexander D. ^[4]; Bissell, Mina J. ^[2]; Attardi, Laura D. ^[3]

Stanford University, CA (United States); DOE/OSTI
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Stanford University, CA (United States)
University of California, Davis, CA (United States)

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. 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. 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. 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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: American Cancer Society; National Cancer Institute; National Institutes of Health; Susan G. Komen Foundation; USDOD; USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1626698

Journal Information:: Breast Cancer Research, Journal Name: Breast Cancer Research Journal Issue: 2 Vol. 14; ISSN 1465-542X

Publisher:: BioMed CentralCopyright Statement

Country of Publication:: United States

Language:: English

References (57)

Monoclonal antibody mapping of keratins 8 and 17 and of vimentin in normal human mammary gland, benign tumors, dysplasias and breast cancer Guelstein, V. I.; Tchypysheva, T. A.; Ermilova, V. D. International Journal of Cancer, Vol. 42, Issue 2 https://doi.org/10.1002/ijc.2910420202	journal	August 1988
E-cadherin expression in bladder cancer using formalin-fixed, paraffin-embedded tissues: Correlation with histopathological grade, tumour stage and survival Syrigos, Konstantinos N.; Krausz, Thomas; Waxman, Jonathan International Journal of Cancer, Vol. 64, Issue 6 https://doi.org/10.1002/ijc.2910640603	journal	December 1995
Molecular aspects of early stages of breast cancer progression Smith, Helene S.; Lu, You; Deng, Guoren Journal of Cellular Biochemistry, Vol. 53, Issue S17G https://doi.org/10.1002/jcb.240531128	journal	January 1993
Reduced p120ctn expression correlates with poor survival in patients with adenocarcinoma of the gastroesophageal junction Wijnhoven, Bas P. L.; Pignatelli, Massimo; Dinjens, Winand N. M. Journal of Surgical Oncology, Vol. 92, Issue 2 https://doi.org/10.1002/jso.20344	journal	January 2005
Genetic manipulation of mammary epithelium by transplantation Edwards, Paul A. W.; Abram, Clare L.; Bradbury, Jane M. Journal of Mammary Gland Biology and Neoplasia, Vol. 1, Issue 1 https://doi.org/10.1007/bf02096304	journal	January 1996
Extracellular Matrix Composition Reveals Complex and Dynamic Stromal-Epithelial Interactions in the Mammary Gland Maller, Ori; Martinson, Holly; Schedin, Pepper Journal of Mammary Gland Biology and Neoplasia, Vol. 15, Issue 3 https://doi.org/10.1007/s10911-010-9189-6	journal	September 2010
A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes Neve, Richard M.; Chin, Koei; Fridlyand, Jane Cancer Cell, Vol. 10, Issue 6 https://doi.org/10.1016/j.ccr.2006.10.008	journal	December 2006
CD4+ T Cells Regulate Pulmonary Metastasis of Mammary Carcinomas by Enhancing Protumor Properties of Macrophages DeNardo, David G.; Barreto, Jairo B.; Andreu, Pauline Cancer Cell, Vol. 16, Issue 2 https://doi.org/10.1016/j.ccr.2009.06.018	journal	August 2009
Perp Is a p63-Regulated Gene Essential for Epithelial Integrity Ihrie, Rebecca A.; Marques, Michelle R.; Nguyen, Bichchau T. Cell, Vol. 120, Issue 6 https://doi.org/10.1016/j.cell.2005.01.008	journal	March 2005
Expression of p53-induced apoptosis effector PERP in primary uveal melanomas: Downregulation is associated with aggressive type Paraoan, Luminita; Gray, Donna; Hiscott, Paul Experimental Eye Research, Vol. 83, Issue 4 https://doi.org/10.1016/j.exer.2006.04.016	journal	October 2006
Environment, inflammation, and cancer Sansone, Pasquale; Bromberg, Jacqueline Current Opinion in Genetics & Development, Vol. 21, Issue 1 https://doi.org/10.1016/j.gde.2010.11.001	journal	February 2011
Biogenesis and function of mouse mammary epithelium depends on the presence of functional α-catenin Nemade, Rashmi V.; Bierie, Brian; Nozawa, Masahiro Mechanisms of Development, Vol. 121, Issue 1 https://doi.org/10.1016/j.mod.2003.09.007	journal	January 2004
The MAPKERK-1,2 pathway integrates distinct and antagonistic signals from TGFα and FGF7 in morphogenesis of mouse mammary epithelium Fata, Jimmie E.; Mori, Hidetoshi; Ewald, Andrew J. Developmental Biology, Vol. 306, Issue 1 https://doi.org/10.1016/j.ydbio.2007.03.013	journal	June 2007
Downregulation and abnormal expression of E-cadherin and β-catenin in nasopharyngeal carcinoma: Close association with advanced disease stage and lymph node metastasis Zheng, Zhong; Pan, Jie; Chu, Bin Human Pathology, Vol. 30, Issue 4 https://doi.org/10.1016/s0046-8177(99)90123-5	journal	April 1999
Tumor-Associated Macrophages in Breast Cancer Leek, Russell D.; Harris, Adrian L. Journal of Mammary Gland Biology and Neoplasia, Vol. 7, Issue 2, p. 177-189 https://doi.org/10.1023/a:1020304003704	journal	January 2002
p63 is a p53 homologue required for limb and epidermal morphogenesis Mills, Alea A.; Zheng, Binhai; Wang, Xiao-Jing Nature, Vol. 398, Issue 6729 https://doi.org/10.1038/19531	journal	April 1999
p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development Yang, Annie; Schweitzer, Ronen; Sun, Deqin Nature, Vol. 398, Issue 6729 https://doi.org/10.1038/19539	journal	April 1999
Desmosomal adhesion regulates epithelial morphogenesis and cell positioning Runswick, Sarah K.; O'Hare, Mike J.; Jones, Louise Nature Cell Biology, Vol. 3, Issue 9 https://doi.org/10.1038/ncb0901-823	journal	August 2001
Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer Jonkers, Jos; Meuwissen, Ralph; van der Gulden, Hanneke Nature Genetics, Vol. 29, Issue 4 https://doi.org/10.1038/ng747	journal	November 2001
Modelling glandular epithelial cancers in three-dimensional cultures Debnath, Jayanta; Brugge, Joan S. Nature Reviews Cancer, Vol. 5, Issue 9 https://doi.org/10.1038/nrc1695	journal	September 2005
Desmosomes: new perpetrators in tumour suppression Dusek, Rachel L.; Attardi, Laura D. Nature Reviews Cancer, Vol. 11, Issue 5 https://doi.org/10.1038/nrc3051	journal	April 2011
Desmosomes: New Perspectives on a Classic Green, Kathleen J.; Simpson, Cory L. Journal of Investigative Dermatology, Vol. 127, Issue 11 https://doi.org/10.1038/sj.jid.5701015	journal	November 2007
Changes in adhesive properties of epithelial cells during early morphogenesis of the mammary gland Nanba, Daisuke; Nakanishi, Yasuo; Hieda, Yohki Development, Growth and Differentiation, Vol. 43, Issue 5 https://doi.org/10.1046/j.1440-169x.2001.00596.x	journal	October 2001
Self-organization is a dynamic and lineage-intrinsic property of mammary epithelial cells Chanson, L.; Brownfield, D.; Garbe, J. C. Proceedings of the National Academy of Sciences, Vol. 108, Issue 8 https://doi.org/10.1073/pnas.1019556108	journal	February 2011
The magical touch: Genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin Vasioukhin, V.; Degenstein, L.; Wise, B. Proceedings of the National Academy of Sciences, Vol. 96, Issue 15 https://doi.org/10.1073/pnas.96.15.8551	journal	July 1999
Targeted expression of stromelysin-1 in mammary gland provides evidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement membrane for tissue-specific gene expression [published erratum appears in J Cell Biol 1996 Feb;132(4):following 752] Sympson, C. J. The Journal of Cell Biology, Vol. 125, Issue 3 https://doi.org/10.1083/jcb.125.3.681	journal	May 1994
The estrogen-dependent c-JunER protein causes a reversible loss of mammary epithelial cell polarity involving a destabilization of adherens junctions. Fialka, I.; Schwarz, H.; Reichmann, E. Journal of Cell Biology, Vol. 132, Issue 6 https://doi.org/10.1083/jcb.132.6.1115	journal	March 1996
CELL CONTACTS IN THE MOUSE MAMMARY GLAND: I. Normal Gland in Postnatal Development and the Secretory Cycle Pitelka, D. R. The Journal of Cell Biology, Vol. 56, Issue 3 https://doi.org/10.1083/jcb.56.3.797	journal	March 1973
p63 is the molecular switch for initiation of an epithelial stratification program Koster, M. I. Genes & Development, Vol. 18, Issue 2 https://doi.org/10.1101/gad.1165104	journal	January 2004
E-cadherin expression in invasive non-lobular carcinoma of the breast and its prognostic significance Rakha, E. A.; Abd El Rehim, D.; Pinder, S. E. Histopathology, Vol. 46, Issue 6 https://doi.org/10.1111/j.1365-2559.2005.02156.x	journal	June 2005
Macrophages Regulate the Angiogenic Switch in a Mouse Model of Breast Cancer Lin, E. Y.; Li, J. -F.; Gnatovskiy, L. Cancer Research, Vol. 66, Issue 23 https://doi.org/10.1158/0008-5472.can-06-1278	journal	November 2006
The cadherin-catenin adhesion system in signaling and cancer Conacci-Sorrell, Maralice; Zhurinsky, Jacob; Ben-Ze’ev, Avri Journal of Clinical Investigation, Vol. 109, Issue 8 https://doi.org/10.1172/jci0215429	journal	April 2002
Specific demonstration of myoepithelial cells by anti-alpha smooth muscle actin antibody. Gugliotta, P.; Sapino, A.; Macrí, L. Journal of Histochemistry & Cytochemistry, Vol. 36, Issue 6 https://doi.org/10.1177/36.6.3367051	journal	June 1988
Myoepithelial cells: good fences make good neighbors Adriance, Melissa C.; Inman, Jamie L.; Petersen, Ole W. Breast Cancer Research, Vol. 7, Issue 5 https://doi.org/10.1186/bcr1286	journal	July 2005
Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression DeNardo, David G.; Coussens, Lisa M. Breast Cancer Research, Vol. 9, Issue 4 https://doi.org/10.1186/bcr1746	journal	August 2007
High-Throughput Tissue Microarray Analysis Used to Evaluate Biology and Prognostic Significance of the E-Cadherin Pathway in Non–Small-Cell Lung Cancer Bremnes, R. M.; Veve, R.; Gabrielson, E. Journal of Clinical Oncology, Vol. 20, Issue 10 https://doi.org/10.1200/jco.2002.08.159	journal	May 2002
Gene Expression Profiling of Localized Esophageal Carcinomas: Association With Pathologic Response to Preoperative Chemoradiation Luthra, Rajyalakshmi; Wu, Tsung-Teh; Luthra, Madan G. Journal of Clinical Oncology, Vol. 24, Issue 2 https://doi.org/10.1200/jco.2005.03.3688	journal	January 2006
A β-catenin survival signal is required for normal lobular development in the mammary gland Tepera, Stacey B.; McCrea, Pierre D.; Rosen, Jeffrey M. Journal of Cell Science, Vol. 116, Issue 6 https://doi.org/10.1242/jcs.00334	journal	March 2003
Genetic Deletion of the Desmosomal Component Desmoplakin Promotes Tumor Microinvasion in a Mouse Model of Pancreatic Neuroendocrine Carcinogenesis Chun, Matthew G. H.; Hanahan, Douglas PLoS Genetics, Vol. 6, Issue 9 https://doi.org/10.1371/journal.pgen.1001120	journal	September 2010
Loss of the p53/p63 Regulated Desmosomal Protein Perp Promotes Tumorigenesis Beaudry, Veronica G.; Jiang, Dadi; Dusek, Rachel L. PLoS Genetics, Vol. 6, Issue 10 https://doi.org/10.1371/journal.pgen.1001168	journal	October 2010
Down-regulation of the desmosomal cadherin desmocollin 3 in human breast cancer Klus, Gregory; Rokaeus, Nina; Bittner, Michael International Journal of Oncology https://doi.org/10.3892/ijo.19.1.169	journal	July 2001
The Cleared Mammary Fat Pad and the Transplantation of Mammary Gland Morphological Structures and Cells Young, Lawrence J. T. Methods in Mammary Gland Biology and Breast Cancer Research https://doi.org/10.1007/978-1-4615-4295-7_6	book	January 2000
Genetic manipulation of mammary epithelium by transplantation Edwards, Paul A. W.; Abram, Clare L.; Bradbury, Jane M. Journal of Mammary Gland Biology and Neoplasia, Vol. 1, Issue 1 https://doi.org/10.1007/BF02096304	journal	January 1996
Downregulation and abnormal expression of E-cadherin and β-catenin in nasopharyngeal carcinoma: Close association with advanced disease stage and lymph node metastasis Zheng, Zhong; Pan, Jie; Chu, Bin Human Pathology, Vol. 30, Issue 4 https://doi.org/10.1016/S0046-8177(99)90123-5	journal	April 1999
The immunohistochemical expression of desmoplakin and its role in vivo in the progression and metastasis of breast cancer Davies, E. L.; Gee, J. M. W.; Cochrane, R. A. European Journal of Cancer, Vol. 35, Issue 6 https://doi.org/10.1016/S0959-8049(99)00031-3	journal	June 1999
Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis Derksen, Patrick W. B.; Liu, Xiaoling; Saridin, Francis Cancer Cell, Vol. 10, Issue 5 https://doi.org/10.1016/j.ccr.2006.09.013	journal	November 2006
Tumor-Associated Macrophages in Breast Cancer Leek, Russell D.; Harris, Adrian L. Journal of Mammary Gland Biology and Neoplasia, Vol. 7, Issue 2, p. 177-189 https://doi.org/10.1023/A:1020304003704	journal	January 2002
β-Catenin and Tcfs in Mammary Development and Cancer Hatsell, Sarah; Rowlands, Tracey; Hiremath, Minoti Journal of Mammary Gland Biology and Neoplasia, Vol. 8, Issue 2, p. 145-158 https://doi.org/10.1023/A:1025944723047	journal	January 2003
Loss of the Desmosomal Protein Perp Enhances the Phenotypic Effects of Pemphigus Vulgaris Autoantibodies Nguyen, Bichchau; Dusek, Rachel L.; Beaudry, Veronica G. Journal of Investigative Dermatology, Vol. 129, Issue 7 https://doi.org/10.1038/jid.2008.419	journal	July 2009
Identification of Desmogleins as Disease Targets Simpson, Cory L.; Green, Kathleen J. Journal of Investigative Dermatology, Vol. 127 https://doi.org/10.1038/sj.skinbio.6250004	journal	January 2007
Changes in adhesive properties of epithelial cells during early morphogenesis of the mammary gland Nanba, Daisuke; Nakanishi, Yasuo; Hieda, Yohki Development, Growth and Differentiation, Vol. 43, Issue 5 https://doi.org/10.1046/j.1440-169X.2001.00596.x	journal	October 2001
PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family Attardi, Laura D.; Reczek, Elizabeth E.; Cosmas, Corinna Genes & Development, Vol. 14, Issue 6 https://doi.org/10.1101/gad.14.6.704	journal	March 2000
In Vivo Function of Desmosomes Cheng, Xing; Koch, Peter J. The Journal of Dermatology, Vol. 31, Issue 3 https://doi.org/10.1111/j.1346-8138.2004.tb00654.x	journal	March 2004
Macrophages Regulate the Angiogenic Switch in a Mouse Model of Breast Cancer Lin, E. Y.; Li, J. -F.; Gnatovskiy, L. Cancer Research, Vol. 66, Issue 23 https://doi.org/10.1158/0008-5472.CAN-06-1278	journal	November 2006
The cadherin-catenin adhesion system in signaling and cancer Conacci-Sorrell, Maralice; Zhurinsky, Jacob; Ben-Ze’ev, Avri Journal of Clinical Investigation, Vol. 109, Issue 8 https://doi.org/10.1172/JCI0215429	journal	April 2002
High-Throughput Tissue Microarray Analysis Used to Evaluate Biology and Prognostic Significance of the E-Cadherin Pathway in Non–Small-Cell Lung Cancer Bremnes, R. M.; Veve, R.; Gabrielson, E. Journal of Clinical Oncology, Vol. 20, Issue 10 https://doi.org/10.1200/JCO.2002.08.159	journal	May 2002
Gene Expression Profiling of Localized Esophageal Carcinomas: Association With Pathologic Response to Preoperative Chemoradiation Luthra, Rajyalakshmi; Wu, Tsung-Teh; Luthra, Madan G. Journal of Clinical Oncology, Vol. 24, Issue 2 https://doi.org/10.1200/JCO.2005.03.3688	journal	January 2006

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Caspase-1 is a novel target of p63 in tumor suppression Celardo, I.; Grespi, F.; Antonov, A. Cell Death & Disease, Vol. 4, Issue 5 https://doi.org/10.1038/cddis.2013.175	journal	May 2013
Downregulation ofHlxClosely Related to the Decreased Expressions ofT-betandRunx3in Patients with Gastric Cancer May Be Associated with a Pathological Event Leading to the Imbalance of Th1/Th2 Xu, Yan; Gao, Jingjing; Su, Zhaoliang Clinical and Developmental Immunology, Vol. 2012 https://doi.org/10.1155/2012/949821	journal	January 2012
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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
human breast cancer cell line
mammary epithelial cell
mammary epithelium
mammary gland
myoepithelial cell
oncology