title: Nuclear Localized LSR: A Novel Regulator of Breast Cancer Behavior and Tumorigenesis.
abstract: Lipolysis-stimulated lipoprotein receptor (LSR) has been found in the plasma membrane and is believed to function in lipoprotein endocytosis and tight junctions. Given the impact of cellular metabolism and junction signaling pathways on tumor phenotypes and patient outcome, it is important to understand how LSR cellular localization mediates its functions. We conducted localization studies, evaluated DNA binding, and examined the effects of nuclear LSR in cells, xenografts, and clinical specimens. We found LSR within the membrane, cytoplasm, and the nucleus of breast cancer cells representing multiple intrinsic subtypes. Chromatin immunoprecipitation (ChIP) showed direct binding of LSR to DNA, and sequence analysis identified putative functional motifs and post-translational modifications of the LSR protein. While neither overexpression of transcript variants, nor pharmacologic manipulation of post-translational modification significantly altered localization, inhibition of nuclear export enhanced nuclear localization, suggesting a mechanism for nuclear retention. Coimmunoprecipitation and proximal ligation assays indicated LSR-pericentrin interactions, presenting potential mechanisms for nuclear-localized LSR. The clinical significance of LSR was evaluated using data from over 1,100 primary breast tumors, which showed high LSR levels in basal-like tumors and tumors from African-Americans. In tumors histosections, nuclear localization was significantly associated with poor outcomes. Finally, in vivo xenograft studies revealed that basal-like breast cancer cells that overexpress LSR exhibited both membrane and nuclear localization, and developed tumors with 100% penetrance, while control cells lacking LSR developed no tumors. These results show that nuclear LSR alters gene expression and may promote aggressive cancer phenotypes.
  
  
  
  LSR functions in the promotion of aggressive breast cancer phenotypes and poor patient outcome via differential subcellular localization to alter cell signaling, bioenergetics, and gene expression. Mol Cancer Res; 15(2); 165-78. ©2016 AACR.
authors.affiliation: Department of Biology, North Carolina Central University, Durham, North Carolina.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Denise K
authors.initials: DK
authors.lastname: Reaves
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hoadley
authors.affiliation: Department of Biology, North Carolina Central University, Durham, North Carolina.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Katerina D
authors.initials: KD
authors.lastname: Fagan-Solis
authors.affiliation: Center for Human Health and the Environment, Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina.
authors.forename: Dereje D
authors.initials: DD
authors.lastname: Jima
authors.affiliation: Center for Human Health and the Environment, Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina.
authors.forename: Michael
authors.initials: M
authors.lastname: Bereman
authors.affiliation: Department of Biology, North Carolina Central University, Durham, North Carolina.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Lynnelle
authors.initials: L
authors.lastname: Thorpe
authors.affiliation: Department of Biology, North Carolina Central University, Durham, North Carolina.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Jyla
authors.initials: J
authors.lastname: Hicks
authors.affiliation: Department of Biology, North Carolina Central University, Durham, North Carolina.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: David
authors.initials: D
authors.lastname: McDonald
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Troester
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Department of Biology, North Carolina Central University, Durham, North Carolina. jodie.fleming@nccu.edu.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Center for Human Health and the Environment, Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina.
authors.forename: Jodie M
authors.initials: JM
authors.lastname: Fleming
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D011973:Receptors, LDL / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D011973:Receptors, LDL; C085992:lipolysis-stimulated receptor