Human Cripto-1 overexpression in the mouse mammary gland results in the development of hyperplasia and adenocarcinoma

Abstract

Human Cripto-1 (CR-1) is overexpressed in approximately 80% of human breast, colon and lung carcinomas. Mouse Cr-1 upregulation is also observed in a number of transgenic (Tg) mouse mammary tumors. To determine whether CR-1 can alter mammary gland development and/or may contribute to tumorigenesis in vivo, we have generated Tg mouse lines that express human CR-1 under the transcriptional control of the mouse mammary tumor virus (MMTV). Stable Tg MMTV/CR-1 FVB/N lines expressing different levels of CR-1 were analysed. Virgin female MMTV/CR-1 Tg mice exhibited enhanced ductal branching, dilated ducts, intraductal hyperplasia, hyperplastic alveolar nodules and condensation of the mammary stroma. Virgin aged MMTV/CR-1 Tg mice also possessed persistent end buds. In aged multiparous MMTV/ CR-1 mice, the hyperplastic phenotype was most pronounced with multifocal hyperplasias. In the highest CR-1-expressing subline, G4, 38% (12/31) of the multiparous animals aged 12-20 months developed hyperplasias and approximately 33% (11/31) developed papillary adenocarcinomas. The long latency period suggests that additional genetic alterations are required to facilitate mammary tumor formation in conjunction with CR-1. This is the first in vivo study that shows hyperplasia and tumor growth in CR-1-overexpressing animals.

Cripto-1 Alters Keratinocyte Differentiation via Blockade of Transforming Growth Factor-β1 Signaling: Role in Skin Carcinogenesis

“…The overexpression of Cripto-1 induces transformation and enhances cell motility and branching morphogenesis in mouse mammary epithelial cells in vitro (15,16). Our data show for the first time that Cripto-1 expression is elevated in tumor promoter -treated skin and chemically induced mouse skin papillomas.…”

“…Overexpression of Cripto-1 increases cell proliferation, anchorage-independent growth, and transformation of mammary epithelial cells in vitro and causes mammary gland hyperplasia and tumor formation in transgenic MMTV-Cripto-1 mice (15,16).…”

Emerging Roles of Nodal and Cripto-1: From Embryogenesis to Breast Cancer Progression

“…In the MMTV-CR-1 transgenic mouse model, overexpression of Cripto-1 was associated with significantly increased lateral side branching of the developing mammary ducts [82]. In another transgenic model where Cripto-1 expression was driven by the Whey acidic protein promoter, the mammary glands of the transgenic mice overexpressing Cripto-1 were characterized by delayed lobuloalveolar development [83] (Fig.…”

Regulation of Cripto-1 Signaling and Biological Activity by Caveolin-1 in Mammary Epithelial Cells

“…[25][26][27] Furthermore, transgenic mouse models have demonstrated that overexpression of a human CR-1 transgene in the mammary gland under the control of the mouse mammary tumor virus (MMTV) or the whey acidic protein promoter results in multifocal mammary hyperplasias and adenocarcinomas in approximately 30 to 50% of multiparous mice. 28,29 MMTV-CR-1 mice have also been recently shown to develop uterine leiomyosarcomas. 30 The presence of a GPI anchor in the mouse and human Cripto-1 protein suggests that this molecule might localize to lipid rafts, which are cell membrane regions that function as microdomains for a number of signaling molecules that are GPI-linked.…”