title: LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of basal-like breast cancer cells.
abstract: LRIG1 (leucine-rich repeat and immunoglobulin-like domain containing), a member of the LRIG family of transmembrane leucine-rich repeat-containing proteins, is a negative regulator of receptor tyrosine kinase signaling and a tumor suppressor. LRIG1 expression is broadly decreased in human cancer and in breast cancer and low expression of LRIG1 has been linked to decreased relapse-free survival. Recently, low expression of LRIG1 was revealed to be an independent risk factor for breast cancer metastasis and death. These findings suggest that LRIG1 may oppose breast cancer cell motility and invasion, cellular processes that are fundamental to metastasis. However, very little is known of LRIG1 function in this regard. In this study, we demonstrate that LRIG1 is downregulated during epithelial-to-mesenchymal transition (EMT) of human mammary epithelial cells, suggesting that LRIG1 expression may represent a barrier to EMT. Indeed, depletion of endogenous LRIG1 in human mammary epithelial cells expands the stem cell population, augments mammosphere formation and accelerates EMT. Conversely, expression of LRIG1 in highly invasive Basal B breast cancer cells provokes a mesenchymal-to-epithelial transition accompanied by a dramatic suppression of tumorsphere formation and a striking loss of invasive growth in three-dimensional culture. LRIG1 expression perturbs multiple signaling pathways and represses markers and effectors of the mesenchymal state. Furthermore, LRIG1 expression in MDA-MB-231 breast cancer cells significantly slows their growth as tumors, providing the first in vivo evidence that LRIG1 functions as a growth suppressor in breast cancer.
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Yokdang
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hatakeyama
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Wald
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Simion
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Tellez
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA, USA.
authors.forename: D Z
authors.initials: DZ
authors.lastname: Chang
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Swamynathan
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Dermatology, University of California, Davis, Sacramento, CA, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Murphy
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Carraway Iii
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sweeney
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors
chemical_list: C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins; D019859:Proto-Oncogene Proteins c-met