Protein Tyrosine Phosphatase 4A2 Expression Predicts Overall and Disease-Free Survival of Human Breast Cancer and Is Associated with Estrogen and Progestin Receptor Status

Expression of protein tyrosine phosphatase PTP4A2 (also known as PRL2) has been examined in a variety of human carcinomas, although its role in breast cancer remains inconclusive. Since the majority of previous breast cancer studies utilized tissue biopsies composed of heterogeneous cell populations, we hypothesized that an examination of PTP4A2 expression in carcinoma cells isolated by laser capture microdissection (LCM) would provide a more accurate means of assessing its predictive value. From investigations of 247 human breast cancer biopsies collected under standardized, stringent conditions, total RNA was extracted from LCM-procured carcinoma cells to perform microarray analyses to identify gene signatures associated with breast cancer behavior. Expression of PTP4A2 was corroborated by real-time quantitative polymerase chain reaction (qPCR) and referenced to estrogen and progesterone receptor levels. Patient outcomes for overall and disease-free survival were more favorable (p = 0.004 and p = 0.001, respectively) when the expression of PTP4A2 in breast carcinomas was increased compared to patients with biopsies with decreased PTP4A2 levels. PTP4A2 expression determined either by microarray or qPCR was elevated in either estrogen receptor (ER)-positive or progestin receptor (PR)-positive breast cancer biopsies compared to ER-negative or PR-negative biopsies. However, PTP4A2 expression was only correlated with overall survival in PR-positive breast carcinomas. These data suggest that PTP4A2 mRNA expression alone may serve as a biomarker for prediction of a breast cancer patient’s risk of recurrence and overall survival.

[1]  R. Salunga,et al.  Gene expression profiles of human breast cancer progression , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[2]  G. Staal,et al.  Protein tyrosine phosphatase activity as a diagnostic parameter in breast cancer , 1995, Breast Cancer Research and Treatment.

[3]  L. Liotta,et al.  Laser capture microdissection. , 2006, Methods in molecular biology.

[4]  L. Kiesel,et al.  Expression and prognostic impact of the protein tyrosine phosphatases PRL-1, PRL-2, and PRL-3 in breast cancer , 2006, British Journal of Cancer.

[5]  W. McGuire,et al.  Steroid hormone receptors in the management of human breast cancer. , 1980, Annals of clinical research.

[6]  Douglas G Altman,et al.  Reporting recommendations for tumor marker prognostic studies. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  J. Lazo,et al.  Metastasis-associated phosphatase PRL-2 regulates tumor cell migration and invasion , 2011, Oncogene.

[8]  Barry Komm,et al.  Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. , 2003, Endocrinology.

[9]  S. Zhang,et al.  Phosphatase of Regenerating Liver 2 (PRL2) Is Essential for Placental Development by Down-regulating PTEN (Phosphatase and Tensin Homologue Deleted on Chromosome 10) and Activating Akt Protein*♦ , 2012, The Journal of Biological Chemistry.

[10]  R. Bast,et al.  Overexpression of the protein tyrosine phosphatase PTP1B in human breast cancer: association with p185c-erbB-2 protein expression. , 1994, Journal of the National Cancer Institute.

[11]  Arul M Chinnaiyan,et al.  Genes regulated by estrogen in breast tumor cells in vitro are similarly regulated in vivo in tumor xenografts and human breast tumors , 2006, Genome Biology.

[12]  C. Redmond,et al.  Influence of tumor estrogen and progesterone receptor levels on the response to tamoxifen and chemotherapy in primary breast cancer. , 1983, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  E. Diamandis,et al.  Tumor Markers: Physiology, Pathobiology, Technology, and Clinical Applications , 2002 .

[14]  Robert F. Bonner,et al.  Laser Capture Microdissection: Molecular Analysis of Tissue , 1997, Science.

[15]  Timothy Hunter,et al.  Molecular signatures suggest a major role for stromal cells in development of invasive breast cancer , 2009, Breast Cancer Research and Treatment.

[16]  J. Wittliff,et al.  Epidermal growth factor binding by breast tumor biopsies and relationship to estrogen receptor and progestin receptor levels. , 1984, Cancer research.

[17]  M. Shekhar,et al.  Breast stroma plays a dominant regulatory role in breast epithelial growth and differentiation: implications for tumor development and progression. , 2001, Cancer research.

[18]  A. Schally,et al.  Characteristics and distribution of receptors for [d‐trp6]‐ luteinizing hormone‐releasing hormone, somatostatin, epidermal growth factor, and sex steroids in 500 biopsy samples of human breast cancer , 1989, Journal of clinical laboratory analysis.

[19]  S. Hardy,et al.  Inside the human cancer tyrosine phosphatome , 2010, Nature Reviews Cancer.

[20]  Y. Nomura.  [Steroid hormone receptors in breast cancer]. , 1990, Rinsho byori. The Japanese journal of clinical pathology.

[21]  J. Frasor,et al.  Selective Estrogen Receptor Modulators , 2004, Cancer Research.

[22]  L. O’Donnell,et al.  Application of laser-capture microdissection to analysis of gene expression in the testis. , 2008, Progress in histochemistry and cytochemistry.

[23]  Adrian V. Lee,et al.  Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  C. Pallen,et al.  PRL PTPs: mediators and markers of cancer progression , 2008, Cancer and Metastasis Reviews.

[25]  David B. Krizman,et al.  The genetics of cancer—a 3D model , 1999, Nature Genetics.

[26]  Wei Wang,et al.  A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. , 2004, Cancer cell.

[27]  J. Bjorge,et al.  Identification of Protein-tyrosine Phosphatase 1B as the Major Tyrosine Phosphatase Activity Capable of Dephosphorylating and Activating c-Src in Several Human Breast Cancer Cell Lines* , 2000, The Journal of Biological Chemistry.

[28]  Martin Krapcho,et al.  SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations) , 2012 .

[29]  M. Tremblay,et al.  The role of protein tyrosine phosphatase 1B in Ras signaling , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[30]  L. Liotta,et al.  Laser-capture microdissection: opening the microscopic frontier to molecular analysis. , 1998, Trends in genetics : TIG.

[31]  N. Tonks,et al.  Purification of the major protein-tyrosine-phosphatases of human placenta. , 1988, The Journal of biological chemistry.

[32]  M. Gye,et al.  Analysis of estrogen-regulated genes in mouse uterus using cDNA microarray and laser capture microdissection. , 2004, The Journal of endocrinology.

[33]  D. V. Von Hoff,et al.  PRL phosphatases as potential molecular targets in cancer , 2005, Molecular Cancer Therapeutics.

[34]  Robert Clarke,et al.  Estrogen receptor alpha positive breast tumors and breast cancer cell lines share similarities in their transcriptome data structures. , 2006, International journal of oncology.

[35]  B. Kennedy,et al.  Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis , 2007, Nature Genetics.

[36]  S. A. Andres,et al.  Relationships of ESR1 and XBP1 expression in human breast carcinoma and stromal cells isolated by laser capture microdissection compared to intact breast cancer tissue , 2011, Endocrine.

[37]  W. McGuire,et al.  Progesterone receptors and human breast cancer , 2005, Breast Cancer Research and Treatment.

[38]  R. Burgemeister.  New Aspects of Laser Microdissection in Research and Routine , 2005, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[39]  M. Tremblay,et al.  Genetic ablation of protein tyrosine phosphatase 1B accelerates lymphomagenesis of p53-null mice through the regulation of B-cell development. , 2005, Cancer research.

[40]  S. Fuqua,et al.  Phosphorylated and sumoylation-deficient progesterone receptors drive proliferative gene signatures during breast cancer progression , 2012, Breast Cancer Research.

[41]  G. Freiss,et al.  Protein tyrosine phosphatases and breast cancer. , 2004, Critical reviews in oncology/hematology.

[42]  Morag Park,et al.  Overexpression of the protein tyrosine phosphatase PRL-2 correlates with breast tumor formation and progression. , 2010, Cancer research.

[43]  E. Copeland,et al.  Book Review The Breast: Comprehensive management of benign and malignant diseases Second edition. Edited by Kirby I. Bland and Edward M. Copeland III. 1631 pp. in two volumes, illustrated. Philadelphia, W.B. Saunders, 1998. $225. 0-7216-6656-6 , 1999 .

[44]  L. Griffiths,et al.  Differential gene expression in breast cancer cell lines and stroma–tumor differences in microdissected breast cancer biopsies revealed by display array analysis , 2002, International journal of cancer.

[45]  B. Djulbegovic,et al.  Comparison of sex steroid receptor determinations in human breast cancer by enzyme immunoassay and radioligand binding , 1990, Journal of clinical laboratory analysis.

[46]  R. Santen,et al.  Aromatase activity and expression in breast cancer and benign breast tissue stromal cells. , 1997, The Journal of clinical endocrinology and metabolism.

[47]  L. Lessard,et al.  The two faces of PTP1B in cancer. , 2010, Biochimica et biophysica acta.

[48]  S. Yip,et al.  PTP1B: a double agent in metabolism and oncogenesis. , 2010, Trends in biochemical sciences.

[49]  Vladimir B. Bajic,et al.  Dragon ERE Finder version 2: a tool for accurate detection and analysis of estrogen response elements in vertebrate genomes , 2003, Nucleic Acids Res..

[50]  F. Pépin,et al.  Stromal gene expression predicts clinical outcome in breast cancer , 2008, Nature Medicine.

[51]  Young-Bum Kim,et al.  PTP1B regulates leptin signal transduction in vivo. , 2002, Developmental cell.

[52]  B. Kennedy,et al.  Attenuation of Adhesion-dependent Signaling and Cell Spreading in Transformed Fibroblasts Lacking Protein Tyrosine Phosphatase-1B , 2001, The Journal of Biological Chemistry.

[53]  Clifford A. Meyer,et al.  Genome-wide analysis of estrogen receptor binding sites , 2006, Nature Genetics.

[54]  A. Vaquero,et al.  The dual role of sirtuins in cancer. , 2011, Genes & cancer.

[55]  J. Wittliff,et al.  A Five-Gene Model Predicts Clinical Outcome in ER+/PR+, Early-Stage Breast Cancers Treated with Adjuvant Tamoxifen , 2011, Hormones & cancer.

[56]  C. Redmond,et al.  Treatment of primary breast cancer with chemotherapy and tamoxifen. , 1981, The New England journal of medicine.

[57]  B. Neel,et al.  Protein-tyrosine phosphatase 1B is required for HER2/Neu-induced breast cancer. , 2007, Cancer research.

[58]  Robert Clarke,et al.  Gene network signaling in hormone responsiveness modifies apoptosis and autophagy in breast cancer cells , 2009, The Journal of Steroid Biochemistry and Molecular Biology.

[59]  P. Wong,et al.  Dual roles of Nrf2 in cancer. , 2008, Pharmacological research.

[60]  K. Horwitz,et al.  Estradiol regulates different genes in human breast tumor xenografts compared with the identical cells in culture. , 2006, Endocrinology.

[61]  B. Kennedy,et al.  Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. , 2002, Developmental cell.

[62]  Xiao-Jun Ma,et al.  Gene expression profiling of the tumor microenvironment during breast cancer progression , 2009, Breast Cancer Research.

[63]  B. Kennedy,et al.  Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. , 1999, Science.

[64]  S. A. Andres,et al.  Molecular signatures of estrogen receptor-associated genes in breast cancer predict clinical outcome. , 2008, Advances in experimental medicine and biology.

[65]  John N Weinstein,et al.  A stromal gene signature associated with inflammatory breast cancer , 2008, International journal of cancer.

[66]  Young-Bum Kim,et al.  Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice , 2000, Molecular and Cellular Biology.