Wnt pathway component LEF1 mediates tumor cell invasion and is expressed in human and murine breast cancers lacking ErbB2 (her-2/neu) overexpression.

Abstract

This study examines the role of LEF1, a component of the Wnt signaling pathway, in human breast and murine mammary carcinoma and its relationship to ErbB2 (her-2/neu) expression. Mammary tissue and tumors from 5 different Wnt pathway-activated transgenic mouse strains and 5 different ErbB2 pathway-activated transgenic mouse strains were studied for the amount and distribution of expression of beta-catenin and LEF1. Fourteen samples of human infiltrating ductal breast cancer arising from a background of ductal carcinoma in situ (DCIS) were analyzed for LEF1, estrogen and progesterone receptor (ER and PR) and her-2/neu expression. in vitro, the effect of estradiol on LEF1 protein expression was examined in several breast cancer cell lines. The functional role of LEF1 was analyzed by a Matrigel invasion assay following transfection of breast cancer cell lines with either an LEF1 expression construct or a dominant-negative LEF1 construct. A significant (p=0.023) negative correlation between the expression of LEF1 and her-2/neu was observed in human breast cancer. LEF1 was strongly expressed, and beta-catenin had nuclear localization, in mammary tumors derived from Wnt pathway transgenic mice but not in ErbB2 pathway transgenic mice. In estrogen-receptor-positive breast cancer cell lines, LEF1 protein expression increased significantly following estradiol incubation (>200% of baseline). Following transient transfection, overexpression of LEF1 promoted and dominant-negative LEF1 inhibited tumor cell invasion. LEF1, a downstream component of the Wnt signaling pathway, defines a distinct, her-2/neu negative (non-overexpressing) subset of breast/mammary cancers in both humans and mice, mediates breast cancer cell invasion, and may be regulated in part by estradiol.

• Authors: Anthony Nguyen, Andrea Rosner, Tatjana Milovanovic, Christopher Hope, Kestutis Planutis, Baisakhi Saha, Benjaporn Chaiwun, Fritz Lin, S Ashraf Imam, J Lawrence Marsh, Randall F Holcombe
• Journal: International journal of oncology (Int J Oncol) Vol. 27 Issue 4 Pg. 949-56 (Oct 2005) ISSN: 1019-6439 [Print] Greece
• PMID: 16142310 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drug Combinations
• Estrogens
• LEF1 protein, human
• Laminin
• Lef1 protein, mouse
• Lymphoid Enhancer-Binding Factor 1
• Proteoglycans
• Receptors, Estrogen
• Receptors, Progesterone
• Wnt Proteins
• beta Catenin
• matrigel
• Estradiol
• Collagen
• Receptor, ErbB-2

Topics

• Animals
• Blotting, Western
• Breast (metabolism)
• Carcinoma, Ductal, Breast (metabolism)
• Cell Line, Tumor
• Collagen (pharmacology)
• Down-Regulation
• Drug Combinations
• Estradiol (metabolism)
• Estrogens (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• In Situ Hybridization
• Jurkat Cells
• Laminin (pharmacology)
• Lymphoid Enhancer-Binding Factor 1 (metabolism, physiology)
• Mammary Glands, Animal (metabolism)
• Mice
• Mice, Transgenic
• Neoplasm Invasiveness
• Proteoglycans (pharmacology)
• Receptor, ErbB-2 (biosynthesis)
• Receptors, Estrogen (metabolism)
• Receptors, Progesterone (metabolism)
• Signal Transduction
• Time Factors
• Transfection
• Up-Regulation
• Wnt Proteins (metabolism)
• beta Catenin (metabolism)