title: ABCC5 supports osteoclast formation and promotes breast cancer metastasis to bone.
abstract: BACKGROUND
  Bone is the most common site of breast cancer metastasis, and complications associated with bone metastases can lead to a significantly decreased patient quality of life. Thus, it is essential to gain a better understanding of the molecular mechanisms that underlie the emergence and growth of breast cancer skeletal metastases.
  
  
  METHODS
  To search for novel molecular mediators that influence breast cancer bone metastasis, we generated gene-expression profiles from laser-capture microdissected trephine biopsies of both breast cancer bone metastases and independent primary breast tumors that metastasized to bone. Bioinformatics analysis identified genes that are differentially expressed in breast cancer bone metastases compared with primary, bone-metastatic breast tumors.
  
  
  RESULTS
  ABCC5, an ATP-dependent transporter, was found to be overexpressed in breast cancer osseous metastases relative to primary breast tumors. In addition, ABCC5 was significantly upregulated in human and mouse breast cancer cell lines with high bone-metastatic potential. Stable knockdown of ABCC5 substantially reduced bone metastatic burden and osteolytic bone destruction in mice. The decrease in osteolysis was further associated with diminished osteoclast numbers in vivo. Finally, conditioned media from breast cancer cells with reduced ABCC5 expression failed to induce in vitro osteoclastogenesis to the same extent as conditioned media from breast cancer cells expressing ABCC5.
  
  
  CONCLUSIONS
  Our data suggest that ABCC5 functions as a mediator of breast cancer skeletal metastasis. ABCC5 expression in breast cancer cells is important for efficient osteoclast-mediated bone resorption. Hence, ABCC5 may be a potential therapeutic target for breast cancer bone metastasis.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Mourskaia
authors.forename: Eitan
authors.initials: E
authors.lastname: Amir
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Dong
authors.forename: Kerstin
authors.initials: K
authors.lastname: Tiedemann
authors.forename: Sean
authors.initials: S
authors.lastname: Cory
authors.forename: Atilla
authors.initials: A
authors.lastname: Omeroglu
authors.forename: Nicholas
authors.initials: N
authors.lastname: Bertos
authors.forename: Véronique
authors.initials: V
authors.lastname: Ouellet
authors.forename: Mark
authors.initials: M
authors.lastname: Clemons
authors.forename: George L
authors.initials: GL
authors.lastname: Scheffer
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.forename: Michael
authors.initials: M
authors.lastname: Hallett
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Komarova
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siegel
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary*; D001842:Bone and Bones / Q000473:pathology; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics*; D010010:Osteoclasts / Q000473:pathology*; D010014:Osteolysis / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D014057:Tomography, X-Ray Computed
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; D034741:RNA, Small Interfering; C120809:ABCC5 protein, human