PMID- 29844572
OWN - NLM
STAT- MEDLINE
DCOM- 20190227
LR  - 20190523
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 37
IP  - 37
DP  - 2018 Sep
TI  - RANK-c attenuates aggressive properties of ER-negative breast cancer by 
      inhibiting NF-kappaB activation and EGFR signaling.
PG  - 5101-5114
LID - 10.1038/s41388-018-0324-y [doi]
AB  - The RANK/RANKL axis emerges as a key regulator of breast cancer initiation, 
      progression, and metastasis. RANK-c is a RANK receptor isoform produced through 
      alternative splicing of the TNFRSF11A (RANK) gene and a dominant-negative 
      regulator of RANK-induced nuclear factor-kappaB (NF-kappaB) activation. Here we report 
      that RANK-c transcript is expressed in 3.2% of cases in The Cancer Genome Atlas 
      breast cancer cohort evenly between ER-positive and ER-negative cases. 
      Nevertheless, the ratio of RANK to RANK-c (RANK/RANK-c) is increased in 
      ER-negative breast cancer cell lines compared to ER-positive breast cancer cell 
      lines. In addition, forced expression of RANK-c in ER-negative breast cancer cell 
      lines inhibited stimuli-induced NF-kappaB activation and attenuated migration, 
      invasion, colony formation, and adhesion of cancer cells. Further, RANK-c 
      expression in MDA-MB-231 cells inhibited lung metastasis and colonization in 
      vivo. The RANK-c-mediated inhibition of cancer cell aggressiveness and nuclear 
      factor-kappaB (NF-kappaB) activation in breast cancer cells seems to rely on a RANK-c/TNF 
      receptor-associated factor-2 (TRAF2) protein interaction. This was further 
      confirmed by a mutated RANK-c that is unable to interact with TRAF2 and abolishes 
      the ability to attenuate NF-kappaB activation, migration, and invasion. Additional 
      protein interaction characterization revealed epidermal growth factor receptor 
      (EGFR) as a novel interacting partner for RANK-c in breast cancer cells with a 
      negative effect on EGFR phosphorylation and EGF-dependent downstream signaling 
      pathway activation. Our findings further elucidate the complex molecular biology 
      of the RANKL/RANK system in breast cancer and provide preliminary data for RANK-c 
      as a possible marker for disease progression and aggressiveness.
FAU - Sirinian, Chaido
AU  - Sirinian C
AD  - Clinical and Molecular Oncology Laboratory, Division of Oncology, Department of 
      Medicine, University of Patras, Patras, Greece.
FAU - Papanastasiou, Anastasios D
AU  - Papanastasiou AD
AD  - Clinical and Molecular Oncology Laboratory, Division of Oncology, Department of 
      Medicine, University of Patras, Patras, Greece. apapanasta@upnet.gr.
FAU - Schizas, Michail
AU  - Schizas M
AD  - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
FAU - Spella, Magda
AU  - Spella M
AD  - Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, 
      Faculty of Medicine, University of Patras, Patras, Greece.
FAU - Stathopoulos, Georgios T
AU  - Stathopoulos GT
AUID- ORCID: 0000-0002-9215-6461
AD  - Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, 
      Faculty of Medicine, University of Patras, Patras, Greece.
FAU - Repanti, Maria
AU  - Repanti M
AD  - Department of Pathology, Patras General Hospital, Patras, Greece.
FAU - Zarkadis, Ioannis K
AU  - Zarkadis IK
AD  - Department of Biology, School of Medicine, University of Patras, Patras, Greece.
FAU - King, Tari A
AU  - King TA
AD  - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
AD  - Surgical Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, 
      Harvard Medical School, Boston, MA, USA.
FAU - Kalofonos, Haralabos P
AU  - Kalofonos HP
AD  - Clinical and Molecular Oncology Laboratory, Division of Oncology, Department of 
      Medicine, University of Patras, Patras, Greece.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180529
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (NF-kappa B)
RN  - 0 (RANK Ligand)
RN  - 0 (Receptor Activator of Nuclear Factor-kappa B)
RN  - 0 (Receptors, Estrogen)
RN  - 0 (Tnfrsf11a protein, mouse)
RN  - EC 2.7.10.1 (EGFR protein, mouse)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Animals
MH  - Breast Neoplasms/*metabolism
MH  - Cell Line, Tumor
MH  - ErbB Receptors/*metabolism
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/physiology
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - NF-kappa B/*metabolism
MH  - RANK Ligand/metabolism
MH  - Receptor Activator of Nuclear Factor-kappa B/*metabolism
MH  - Receptors, Estrogen/*metabolism
MH  - Signal Transduction/*physiology
EDAT- 2018/05/31 06:00
MHDA- 2019/02/28 06:00
CRDT- 2018/05/31 06:00
PHST- 2017/08/09 00:00 [received]
PHST- 2018/04/21 00:00 [accepted]
PHST- 2018/04/21 00:00 [revised]
PHST- 2018/05/31 06:00 [pubmed]
PHST- 2019/02/28 06:00 [medline]
PHST- 2018/05/31 06:00 [entrez]
AID - 10.1038/s41388-018-0324-y [pii]
AID - 10.1038/s41388-018-0324-y [doi]
PST - ppublish
SO  - Oncogene. 2018 Sep;37(37):5101-5114. doi: 10.1038/s41388-018-0324-y. Epub 2018 
      May 29.