Peroxisome proliferator-activated receptor gamma in human breast carcinoma: a modulator of estrogenic actions.

It has been reported that agonists of peroxisome proliferator-activated receptor gamma (PPARgamma) inhibit proliferation of breast carcinoma cells, but the biological significance of PPARgamma remains undetermined in human breast carcinomas. Therefore, we immunolocalized PPARgamma in 238 human breast carcinoma tissues. PPARgamma immunoreactivity was detected in 42% of carcinomas, and was significantly associated with the status of estrogen receptor (ER) alpha, ERbeta, progesterone receptor, retinoic X receptors, p21 or p27, and negatively correlated with histological grade or cyclooxygenase-2 status. PPARgamma immunoreactivity was significantly associated with an improved clinical outcome of breast carcinoma patients by univariate analysis, and multivariate analysis demonstrated that PPARgamma immunoreactivity was an independent prognostic factor for overall survival in ERalpha-positive patients. We then examined possible mechanisms of modulation by PPARgamma on estrogenic actions in MCF-7 breast carcinoma cells. A PPARgamma activator, 15-deoxy-Delta(12,14)- prostaglandin J(2) (15d-PGJ(2)), significantly inhibited estrogen-responsive element-dependent transactivation by estradiol in MCF-7 cells, which was blocked by addition of a PPARgamma antagonist GW9662. Subsequent study, employing a custom-made microarray focused on estrogen-responsive genes, revealed that mRNA expression was significantly regulated by estradiol in 49 genes, but this significance vanished on addition of 15d-PGJ(2) in 16 out of 49 (33%) genes. These findings were confirmed by real-time PCR in 11 genes. 15d-PGJ(2) significantly inhibited estrogen-mediated proliferation of MCF-7 cells, and caused accumulation of p21 and p27 protein. These results suggest that PPARgamma is mainly expressed in well-differentiated and ER-positive breast carcinomas, and modulates estrogenic actions.

[1]  M. Kilgore,et al.  The Increased Expression of Peroxisome Proliferator-Activated Receptor-γ1 in Human Breast Cancer Is Mediated by Selective Promoter Usage , 2004, Cancer Research.

[2]  Martin C Frith,et al.  Genomic targets of nuclear estrogen receptors. , 2004, Molecular endocrinology.

[3]  G. Watkins,et al.  The localisation and reduction of nuclear staining of PPARgamma and PGC-1 in human breast cancer. , 2004, Oncology reports.

[4]  D. Crowe,et al.  A retinoid X receptor (RXR)-selective retinoid reveals that RXR-α is potentially a therapeutic target in breast cancer cell lines, and that it potentiates antiproliferative and apoptotic responses to peroxisome proliferator-activated receptor ligands , 2004, Breast Cancer Research.

[5]  John H. White,et al.  Genome-wide identification of high-affinity estrogen response elements in human and mouse. , 2004, Molecular endocrinology.

[6]  M. Kurosumi,et al.  Prediction of prognosis of estrogen receptor‐positive breast cancer with combination of selected estrogen‐regulated genes , 2004, Cancer science.

[7]  A. Sugawara,et al.  Expression of peroxisome proliferator-activated receptor isoform proteins in the rat kidney. , 2004, Hypertension research : official journal of the Japanese Society of Hypertension.

[8]  P. Fisher,et al.  Up-regulation of p21 Gene Expression by Peroxisome Proliferator-Activated Receptor γ in Human Lung Carcinoma Cells , 2004, Clinical Cancer Research.

[9]  G. Firestone,et al.  Estrogen Receptor β Inhibits Human Breast Cancer Cell Proliferation and Tumor Formation by Causing a G2 Cell Cycle Arrest , 2004, Cancer Research.

[10]  R. Mansel,et al.  Expression of peroxisome‐proliferator activated receptor‐gamma (PPARγ) and the PPARγ co‐activator, PGC‐1, in human breast cancer correlates with clinical outcomes , 2003 .

[11]  D. Gold,et al.  Activation of peroxisome proliferator-activated receptor gamma by a novel synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest and apoptosis in breast cancer cells. , 2003, Cancer research.

[12]  J. Shih,et al.  Tumor-associated antigen L6 and the invasion of human lung cancer cells. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[13]  B. Spiegelman,et al.  Use of the Peroxisome Proliferator-Activated Receptor (PPAR) γ Ligand Troglitazone as Treatment for Refractory Breast Cancer: A Phase II Study , 2003, Breast Cancer Research and Treatment.

[14]  K. Tanimoto,et al.  The expression and function of estrogen receptor alpha and beta in human breast cancer and its clinical application. , 2003, Endocrine-related cancer.

[15]  N. Pavlidis,et al.  Clinicopathological study of the expression of hsp27, pS2, cathepsin D and metallothionein in primary invasive breast cancer. , 2003, Breast.

[16]  V. Kosma,et al.  p21WAF1 expression in invasive breast cancer and its association with p53, AP-2, cell proliferation, and prognosis , 2003, Journal of clinical pathology.

[17]  M. Marino,et al.  Synergism between Genomic and Non Genomic Estrogen Action Mechanisms , 2003, IUBMB life.

[18]  S. Safe,et al.  Peroxisome Proliferator-activated Receptor γ Agonists Induce Proteasome-dependent Degradation of Cyclin D1 and Estrogen Receptor α in MCF-7 Breast Cancer Cells , 2003 .

[19]  Y. Yano,et al.  Peroxisome Proliferator‐activated Receptor Gamma Activation Induces Cell Cycle Arrest via the p53‐independent Pathway in Human Anaplastic Thyroid Cancer Cells , 2002, Japanese journal of cancer research : Gann.

[20]  T. Yamori,et al.  Development of cDNA microarray for expression profiling of estrogen-responsive genes. , 2002, Journal of molecular endocrinology.

[21]  Y. Omoto,et al.  Estrogen receptor-mediated effects of tamoxifen on human endometrial cancer cells , 2002, Molecular and Cellular Endocrinology.

[22]  F. Speleman,et al.  Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes , 2002, Genome Biology.

[23]  T. Willson,et al.  Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. , 2002, Biochemistry.

[24]  A. Shuldiner,et al.  The role of peroxisome proliferator-activated receptor gamma in diabetes and obesity , 2002, Current diabetes reports.

[25]  K. Walsh,et al.  Decorin-mediated Signal Transduction in Endothelial Cells , 2001, The Journal of Biological Chemistry.

[26]  S. Nakashima,et al.  MDM2 Enhances the Function of Estrogen Receptor α in Human Breast Cancer Cells , 2001 .

[27]  H. Nischalke,et al.  Semi-quantification of human C-C chemokine mRNAs with reverse transcription/real-time PCR using multi-specific standards. , 2000, Journal of immunological methods.

[28]  H. Peterse,et al.  p27kip1 expression in breast carcinomas: An immunohistochemical study on 512 patients with long‐term follow‐up , 2000 .

[29]  V. Seewaldt,et al.  Peroxisome proliferator-activated receptor gamma activation in human breast cancer. , 1999, International journal of oncology.

[30]  K. Chien,et al.  PPARγ Is Required for Placental, Cardiac, and Adipose Tissue Development , 1999 .

[31]  R. Bouvier,et al.  Differential RNA expression of the pS2 gene in the human benign and malignant prostatic tissue. , 1999, Prostate cancer and prostatic diseases.

[32]  T. Zacharewski,et al.  pS2 (TFF1) levels in human breast cancer tumor samples: correlation with clinical and histological prognostic markers , 1999, Breast Cancer Research and Treatment.

[33]  S. Safe,et al.  Transcriptional Activation of Insulin-Like Growth Factor-Binding Protein-4 by 17β-Estradiol in MCF-7 Cells: Role of Estrogen Receptor-Sp1 Complexes. , 1999, Endocrinology.

[34]  M. Michikawa,et al.  Enhancement of MTT, a tetrazolium salt, exocytosis by amyloid β-protein and chloroquine in cultured rat astrocytes , 1999, Neuroscience Letters.

[35]  H. Sprecher,et al.  Estrogen-induced Production of a Peroxisome Proliferator-activated Receptor (PPAR) Ligand in a PPARγ-expressing Tissue* , 1998, The Journal of Biological Chemistry.

[36]  P. Kolattukudy,et al.  Peroxisome proliferator‐activated receptor γ1 (PPAR‐γ1) as a major PPAR in a tissue in which estrogen induces peroxisome proliferation , 1998 .

[37]  H P Koeffler,et al.  Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[38]  B. Spiegelman,et al.  Terminal differentiation of human breast cancer through PPAR gamma. , 1998, Molecular cell.

[39]  D. Allred,et al.  Prognostic and predictive factors in breast cancer by immunohistochemical analysis. , 1998, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[40]  M. Fan,et al.  Lymph node micrometastases from breast carcinoma , 1997, Cancer.

[41]  S. Safe,et al.  Identification of a functional imperfect estrogen-responsive element in the 5'-promoter region of the human cathepsin D gene. , 1997, Biochemistry.

[42]  A. Marchetti,et al.  Cyclin‐d1‐gene amplification and expression in breast carcinoma: Relation with clinicopathologic characteristics and with retinoblastoma gene product, p53 and p21waf1 immunohistochemical expression , 1997, International journal of cancer.

[43]  J Auwerx,et al.  Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. , 1996, Journal of lipid research.

[44]  R. Evans,et al.  The RXR heterodimers and orphan receptors , 1995, Cell.

[45]  J. Lehmann,et al.  A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation , 1995, Cell.

[46]  W. Wahli,et al.  Signaling cross-talk between peroxisome proliferator-activated receptor/retinoid X receptor and estrogen receptor through estrogen response elements. , 1995, Molecular endocrinology.

[47]  A. Sugawara,et al.  Isoform-specific retinoid-X receptor (RXR) antibodies detect differential expression of RXR proteins in the pituitary gland. , 1995, Endocrinology.

[48]  K. Korach.  Insights from the study of animals lacking functional estrogen receptor. , 1994, Science.

[49]  B. Spiegelman,et al.  mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. , 1994, Genes & development.

[50]  S. Ben‐Sasson,et al.  Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation , 1992, The Journal of cell biology.

[51]  I. Ellis,et al.  Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. , 2002, Histopathology.

[52]  P. Chambon,et al.  Functional domains of the human estrogen receptor , 1987, Cell.

[53]  W. McGuire,et al.  Estrogen control of progesterone receptor in human breast cancer. Correlation with nuclear processing of estrogen receptor. , 1978, The Journal of biological chemistry.

[54]  M. Zanetti,et al.  Estrogen-directed synthesis of specific prostaglandins in uterus. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[55]  G. Firestone,et al.  Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. , 2004, Cancer research.

[56]  T. Okumura,et al.  Growth arrest by troglitazone is mediated by p27Kip1 accumulation, which results from dual inhibition of proteasome activity and Skp2 expression in human hepatocellular carcinoma cells , 2004, International journal of cancer.

[57]  A. Sugawara,et al.  Retinoid Receptors in Human Breast Carcinoma: Possible Modulators of in Situ Estrogen Metabolism , 2004, Breast Cancer Research and Treatment.

[58]  H. Koeffler.  Peroxisome proliferator-activated receptor gamma and cancers. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[59]  R. Mansel,et al.  Expression of peroxisome-proliferator activated receptor-gamma (PPARgamma) and the PPARgamma co-activator, PGC-1, in human breast cancer correlates with clinical outcomes. , 2003, International journal of cancer.

[60]  A. Badawi,et al.  Expression of cyclooxygenase‐2 and peroxisome proliferator‐activated receptor‐γ and levels of prostaglandin E2 and 15‐deoxy‐Δ12,14‐prostaglandin J2 in human breast cancer and metastasis , 2003 .

[61]  H. Koeffler.  Peroxisome proliferator-activated receptor γ and cancers , 2003 .

[62]  S. Safe,et al.  Peroxisome proliferator-activated receptor gamma agonists induce proteasome-dependent degradation of cyclin D1 and estrogen receptor alpha in MCF-7 breast cancer cells. , 2003, Cancer research.

[63]  D. Gold,et al.  Activation of peroxisome proliferator-activated receptor gamma by a novel synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest and apoptosis in breast cancer cells. , 2003, Cancer research.

[64]  S. Saji,et al.  MDM2 enhances the function of estrogen receptor alpha in human breast cancer cells. , 2001, Biochemical and biophysical research communications.

[65]  H. Peterse,et al.  p27(kip1) expression in breast carcinomas: an immunohistochemical study on 512 patients with long-term follow-up. , 2000, International journal of cancer.

[66]  R. Evans,et al.  PPAR gamma is required for placental, cardiac, and adipose tissue development. , 1999, Molecular cell.

[67]  S. Kitano,et al.  G-Protein g 7 Is Down-Regulated in Cancers and Associated with P 27 -induced Growth Arrest , 1999 .

[68]  S. Safe,et al.  Transcriptional activation of insulin-like growth factor-binding protein-4 by 17beta-estradiol in MCF-7 cells: role of estrogen receptor-Sp1 complexes. , 1999, Endocrinology.

[69]  P. Kolattukudy,et al.  Peroxisome proliferator-activated receptor gamma1 (PPAR-gamma1) as a major PPAR in a tissue in which estrogen induces peroxisome proliferation. , 1998, FEBS letters.

[70]  W. Wahli,et al.  Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology. , 1996, Annual review of cell and developmental biology.

[71]  B. O’Malley,et al.  Molecular mechanisms of action of steroid/thyroid receptor superfamily members. , 1994, Annual review of biochemistry.

[72]  M. Rio,et al.  Structure and function of the pS2 gene and estrogen receptor in human breast cancer cells. , 1988, Cancer treatment and research.