Wnt pathway component LEF1 mediates tumor cell invasion and is expressed in human and murine breast cancers lacking ErbB2 (her-2/neu) overexpression.
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.
Nguyen
Anthony
A
Division of Hematology/Oncology, University of California, Irvine, CA, USA.
Rosner
Andrea
A
Milovanovic
Tatjana
T
Hope
Christopher
C
Planutis
Kestutis
K
Saha
Baisakhi
B
Chaiwun
Benjaporn
B
Lin
Fritz
F
Imam
S Ashraf
SA
Marsh
J Lawrence
JL
Holcombe
Randall F
RF
D000818:Animals; D015153:Blotting, Western; D001940:Breast / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism; D045744:Cell Line, Tumor; D003094:Collagen / Q000494:pharmacology; D015536:Down-Regulation; D004338:Drug Combinations; D004958:Estradiol / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D019169:Jurkat Cells; D007797:Laminin / Q000494:pharmacology; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism / Q000502:physiology*; D008321:Mammary Glands, Animal / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D011509:Proteoglycans / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D003094:Collagen; D004338:Drug Combinations; D004958:Estradiol; D004967:Estrogens; D007797:Laminin; D051821:Lymphoid Enhancer-Binding Factor 1; D011509:Proteoglycans; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D051153:Wnt Proteins; D051176:beta Catenin; C497573:LEF1 protein, human; C497574:Lef1 protein, mouse; C059485:matrigel