title: The lipid-transfer protein Nir2 enhances epithelial-mesenchymal transition and facilitates breast cancer metastasis.
abstract: The involvement of epithelial-mesenchymal transition (EMT) in breast cancer metastasis has been demonstrated in many studies. However, the intracellular proteins and signaling pathways that regulate EMT have not been fully identified. Here, we show that the lipid-transfer protein Nir2 (also known as PITPNM1) enhances EMT in mammary epithelial and breast cancer cells. Nir2 overexpression decreases the expression of epithelial markers and concomitantly increases the expression of mesenchymal markers, whereas silencing of Nir2 expression by small hairpin RNA (shRNA) has opposite effects. Additionally, Nir2 expression is increased during EMT and affects cell morphology, whereas Nir2 depletion attenuates growth factor-induced cell migration. These effects of Nir2 on EMT-associated processes are mainly mediated through the PI3K/AKT and the ERK1/2 pathways. Nir2 depletion also inhibits cell invasion in vitro and lung metastasis in animal models. Immunohistochemical analysis of breast cancer tissue samples reveals a correlation between high Nir2 expression and tumor grade, and Kaplan-Meier survival curves correlate Nir2 expression with poor disease outcome. These results suggest that Nir2 not only enhances EMT in vitro and breast cancer metastasis in animal models, but also contributes to breast cancer progression in human patients.
authors.affiliation: Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Omer
authors.initials: O
authors.lastname: Keinan
authors.affiliation: Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Amir
authors.initials: A
authors.lastname: Kedan
authors.affiliation: Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Nancy
authors.initials: N
authors.lastname: Gavert
authors.affiliation: Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Selitrennik
authors.affiliation: Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: SoHui
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and Gynecology, Goethe University Frankfurt, Theodor-Stern Kai 7, 60590 Frankfurt, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Karn
authors.affiliation: Department of Obstetrics and Gynecology, Goethe University Frankfurt, Theodor-Stern Kai 7, 60590 Frankfurt, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Becker
authors.affiliation: Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot 76100, Israel sima.lev@weizmann.ac.il.
authors.forename: Sima
authors.initials: S
authors.lastname: Lev
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; D005136:Eye Proteins; D008565:Membrane Proteins; C113505:PITPNM1 protein, human; C485161:Pitpnm protein, mouse
keywords: EMT; Invasion; Metastasis; Migration; Nir2; PITPNM1