Overexpression of Human Cripto-1 in Transgenic Mice Delays Mammary Gland Development and Differentiation and Induces Mammary Tumorigenesis

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2005 Jul 29

PMID 16049342

Citations 24

Authors

Youping Sun

Luigi Strizzi

Ahmed Raafat

Morihisa Hirota

Caterina Bianco

Lionel Feigenbaum

Nicholas Kenney

Christian Wechselberger

Robert Callahan

David S Salomon

Affiliations

Soon will be listed here.

Abstract

Overexpression of Cripto-1 has been reported in several types of human cancers including breast cancer. To investigate the role of human Cripto-1 (CR-1) in mammary gland development and tumorigenesis, we developed transgenic mice that express the human CR-1 transgene under the regulation of the whey acidic protein (WAP) promoter in the FVB/N mouse background. The CR-1 transgene was detected in the mammary gland of 15-week-old virgin WAP-CR-1 female mice that eventually developed hyperplastic lesions. From mid-pregnancy to early lactation, mammary lobulo-alveolar structures in WAP-CR-1 mice were less differentiated and delayed in their development due to decreased cell proliferation as compared to FVB/N mice. Early involution, due to increased apoptosis, was observed in the mammary glands of WAP-CR-1 mice. Higher levels of phosphorylated AKT and MAPK were detected in mammary glands of multiparous WAP-CR-1 mice as compared to multiparous FVB/N mice suggesting increased cell proliferation and survival of the transgenic mammary gland. In addition, more than half (15 of 29) of the WAP-CR-1 multiparous female mice developed multifocal mammary tumors of mixed histological subtypes. These results demonstrate that overexpression of CR-1 during pregnancy and lactation can lead to alterations in mammary gland development and to production of mammary tumors in multiparous mice.

Citing Articles

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Liver-specific over-expression of Cripto-1 in transgenic mice promotes hepatocyte proliferation and deregulated expression of hepatocarcinogenesis-related genes and signaling pathways.

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CRIPTO antagonist ALK4-Fc inhibits breast cancer cell plasticity and adaptation to stress.

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NOMO-1 gene is deleted in early-onset colorectal cancer.

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