Overexpression of the tumor suppressor gene phosphatase and tensin homologue partially inhibits Wnt-1-induced mammary tumorigenesis

Hong Zhao, Yongzhi Cui, Joelle Dupont, Hui Sun, Lothar Hennighausen, Shoshana Yakar

Research output: Contribution to journalArticle

Abstract

The tumor suppressor phosphatase and tensin homologue (PTEN) is involved in cell proliferation, adhesion, and apoptosis. PTEN overexpression in mammary epithelium leads to reduced cell number and impaired differentiation and secretion. In contrast, overexpression of the proto-oncogene Wnt-1 in mammary epithelium leads to mammary hyperplasia and subsequently focal mammary tumors. To explore the possibility that PTEN intersects with Wnt-induced tumorigenesis, mice that ectopically express PTEN and Wnt-1 in mammary epithelium were generated. PTEN overexpression resulted in an 11% reduction of Wnt-1-induced tumors within a 12-month period and the onset of tumors was delayed from an average of 5.9 to 7.7 months. The rate of tumor growth, measured from 0.5 cm diameter until the tumors reached 1.0 cm diameter, was increased from 8.4 days in Wnt-1 mice to 17.7 days in Wnt-1 mice overexpressing PTEN. Here we show for the first time in vivo that overexpression of PTEN in the Wnt-1 transgenic mice resulted in a marked decrease in the insulin-like growth factor (IGF)-I receptor levels leading to a reduced IGF-I-mediated mitogenesis. Moreover, the percentage of BrdUrd-positive epithelial nuclei was decreased by 48%. β-Catenin immunoreactivity was significantly decreased and the percentage of signal transducer and activator of transcription 5a (stat5a)-positive mammary epithelial cells was increased by 2-fold in Wnt-1 mice overexpressing PTEN. The present study shows that PTEN can partially inhibit the Wnt-1-induced mammary tumorigenesis in early neoplastic stages by blocking the AKT pathway and by reducing the IGF-I receptor levels in mammary gland. This study identifies the PTEN as a therapeutic target for the treatment of mammary cancer and presumably other types of cancer.

Original languageEnglish (US)
Pages (from-to)6864-6873
Number of pages10
JournalCancer Research
Volume65
Issue number15
DOIs
StatePublished - Aug 1 2005

Fingerprint

Tumor Suppressor Genes
Phosphoric Monoester Hydrolases
Carcinogenesis
Breast
Neoplasms
IGF Type 1 Receptor
Epithelium
Tensins
STAT5 Transcription Factor
Breast Neoplasms
Catenins
Proto-Oncogenes
Human Mammary Glands
Insulin-Like Growth Factor I
Cell Adhesion
Transgenic Mice
Hyperplasia
Cell Count
Epithelial Cells
Cell Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Overexpression of the tumor suppressor gene phosphatase and tensin homologue partially inhibits Wnt-1-induced mammary tumorigenesis. / Zhao, Hong; Cui, Yongzhi; Dupont, Joelle; Sun, Hui; Hennighausen, Lothar; Yakar, Shoshana.

In: Cancer Research, Vol. 65, No. 15, 01.08.2005, p. 6864-6873.

Research output: Contribution to journalArticle

Zhao, Hong ; Cui, Yongzhi ; Dupont, Joelle ; Sun, Hui ; Hennighausen, Lothar ; Yakar, Shoshana. / Overexpression of the tumor suppressor gene phosphatase and tensin homologue partially inhibits Wnt-1-induced mammary tumorigenesis. In: Cancer Research. 2005 ; Vol. 65, No. 15. pp. 6864-6873.
@article{d20bc2bcc6df4988a8562654c80c38b4,
title = "Overexpression of the tumor suppressor gene phosphatase and tensin homologue partially inhibits Wnt-1-induced mammary tumorigenesis",
abstract = "The tumor suppressor phosphatase and tensin homologue (PTEN) is involved in cell proliferation, adhesion, and apoptosis. PTEN overexpression in mammary epithelium leads to reduced cell number and impaired differentiation and secretion. In contrast, overexpression of the proto-oncogene Wnt-1 in mammary epithelium leads to mammary hyperplasia and subsequently focal mammary tumors. To explore the possibility that PTEN intersects with Wnt-induced tumorigenesis, mice that ectopically express PTEN and Wnt-1 in mammary epithelium were generated. PTEN overexpression resulted in an 11{\%} reduction of Wnt-1-induced tumors within a 12-month period and the onset of tumors was delayed from an average of 5.9 to 7.7 months. The rate of tumor growth, measured from 0.5 cm diameter until the tumors reached 1.0 cm diameter, was increased from 8.4 days in Wnt-1 mice to 17.7 days in Wnt-1 mice overexpressing PTEN. Here we show for the first time in vivo that overexpression of PTEN in the Wnt-1 transgenic mice resulted in a marked decrease in the insulin-like growth factor (IGF)-I receptor levels leading to a reduced IGF-I-mediated mitogenesis. Moreover, the percentage of BrdUrd-positive epithelial nuclei was decreased by 48{\%}. β-Catenin immunoreactivity was significantly decreased and the percentage of signal transducer and activator of transcription 5a (stat5a)-positive mammary epithelial cells was increased by 2-fold in Wnt-1 mice overexpressing PTEN. The present study shows that PTEN can partially inhibit the Wnt-1-induced mammary tumorigenesis in early neoplastic stages by blocking the AKT pathway and by reducing the IGF-I receptor levels in mammary gland. This study identifies the PTEN as a therapeutic target for the treatment of mammary cancer and presumably other types of cancer.",
author = "Hong Zhao and Yongzhi Cui and Joelle Dupont and Hui Sun and Lothar Hennighausen and Shoshana Yakar",
year = "2005",
month = "8",
day = "1",
doi = "10.1158/0008-5472.CAN-05-0181",
language = "English (US)",
volume = "65",
pages = "6864--6873",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "15",

}

TY - JOUR

T1 - Overexpression of the tumor suppressor gene phosphatase and tensin homologue partially inhibits Wnt-1-induced mammary tumorigenesis

AU - Zhao, Hong

AU - Cui, Yongzhi

AU - Dupont, Joelle

AU - Sun, Hui

AU - Hennighausen, Lothar

AU - Yakar, Shoshana

PY - 2005/8/1

Y1 - 2005/8/1

N2 - The tumor suppressor phosphatase and tensin homologue (PTEN) is involved in cell proliferation, adhesion, and apoptosis. PTEN overexpression in mammary epithelium leads to reduced cell number and impaired differentiation and secretion. In contrast, overexpression of the proto-oncogene Wnt-1 in mammary epithelium leads to mammary hyperplasia and subsequently focal mammary tumors. To explore the possibility that PTEN intersects with Wnt-induced tumorigenesis, mice that ectopically express PTEN and Wnt-1 in mammary epithelium were generated. PTEN overexpression resulted in an 11% reduction of Wnt-1-induced tumors within a 12-month period and the onset of tumors was delayed from an average of 5.9 to 7.7 months. The rate of tumor growth, measured from 0.5 cm diameter until the tumors reached 1.0 cm diameter, was increased from 8.4 days in Wnt-1 mice to 17.7 days in Wnt-1 mice overexpressing PTEN. Here we show for the first time in vivo that overexpression of PTEN in the Wnt-1 transgenic mice resulted in a marked decrease in the insulin-like growth factor (IGF)-I receptor levels leading to a reduced IGF-I-mediated mitogenesis. Moreover, the percentage of BrdUrd-positive epithelial nuclei was decreased by 48%. β-Catenin immunoreactivity was significantly decreased and the percentage of signal transducer and activator of transcription 5a (stat5a)-positive mammary epithelial cells was increased by 2-fold in Wnt-1 mice overexpressing PTEN. The present study shows that PTEN can partially inhibit the Wnt-1-induced mammary tumorigenesis in early neoplastic stages by blocking the AKT pathway and by reducing the IGF-I receptor levels in mammary gland. This study identifies the PTEN as a therapeutic target for the treatment of mammary cancer and presumably other types of cancer.

AB - The tumor suppressor phosphatase and tensin homologue (PTEN) is involved in cell proliferation, adhesion, and apoptosis. PTEN overexpression in mammary epithelium leads to reduced cell number and impaired differentiation and secretion. In contrast, overexpression of the proto-oncogene Wnt-1 in mammary epithelium leads to mammary hyperplasia and subsequently focal mammary tumors. To explore the possibility that PTEN intersects with Wnt-induced tumorigenesis, mice that ectopically express PTEN and Wnt-1 in mammary epithelium were generated. PTEN overexpression resulted in an 11% reduction of Wnt-1-induced tumors within a 12-month period and the onset of tumors was delayed from an average of 5.9 to 7.7 months. The rate of tumor growth, measured from 0.5 cm diameter until the tumors reached 1.0 cm diameter, was increased from 8.4 days in Wnt-1 mice to 17.7 days in Wnt-1 mice overexpressing PTEN. Here we show for the first time in vivo that overexpression of PTEN in the Wnt-1 transgenic mice resulted in a marked decrease in the insulin-like growth factor (IGF)-I receptor levels leading to a reduced IGF-I-mediated mitogenesis. Moreover, the percentage of BrdUrd-positive epithelial nuclei was decreased by 48%. β-Catenin immunoreactivity was significantly decreased and the percentage of signal transducer and activator of transcription 5a (stat5a)-positive mammary epithelial cells was increased by 2-fold in Wnt-1 mice overexpressing PTEN. The present study shows that PTEN can partially inhibit the Wnt-1-induced mammary tumorigenesis in early neoplastic stages by blocking the AKT pathway and by reducing the IGF-I receptor levels in mammary gland. This study identifies the PTEN as a therapeutic target for the treatment of mammary cancer and presumably other types of cancer.

UR - http://www.scopus.com/inward/record.url?scp=23044480599&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=23044480599&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-05-0181

DO - 10.1158/0008-5472.CAN-05-0181

M3 - Article

C2 - 16061670

AN - SCOPUS:23044480599

VL - 65

SP - 6864

EP - 6873

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 15

ER -