title: HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab.
abstract: Although current breast cancer treatment guidelines limit the use of HER2-blocking agents to tumors with HER2 gene amplification, recent retrospective analyses suggest that a wider group of patients may benefit from this therapy. Using breast cancer cell lines, mouse xenograft models and matched human primary and metastatic tissues, we show that HER2 is selectively expressed in and regulates self-renewal of the cancer stem cell (CSC) population in estrogen receptor-positive (ER(+)), HER2(-) luminal breast cancers. Although trastuzumab had no effects on the growth of established luminal breast cancer mouse xenografts, administration after tumor inoculation blocked subsequent tumor growth. HER2 expression is increased in luminal tumors grown in mouse bone xenografts, as well as in bone metastases from patients with breast cancer as compared with matched primary tumors. Furthermore, this increase in HER2 protein expression was not due to gene amplification but rather was mediated by receptor activator of NF-κB (RANK)-ligand in the bone microenvironment. These studies suggest that the clinical efficacy of adjuvant trastuzumab may relate to the ability of this agent to target the CSC population in a process that does not require HER2 gene amplification. Furthermore, these studies support a CSC model in which maximal clinical benefit is achieved when CSC targeting agents are administered in the adjuvant setting. Cancer Res; 73(5); 1635-46. ©2012 AACR.
authors: University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors: Suthinee
authors: S
authors: Ithimakin
authors: Kathleen C
authors: KC
authors: Day
authors: Fayaz
authors: F
authors: Malik
authors: Qin
authors: Q
authors: Zen
authors: Scott J
authors: SJ
authors: Dawsey
authors: Tom F
authors: TF
authors: Bersano-Begey
authors: Ahmed A
authors: AA
authors: Quraishi
authors: Kathleen Woods
authors: KW
authors: Ignatoski
authors: Stephanie
authors: S
authors: Daignault
authors: April
authors: A
authors: Davis
authors: Christopher L
authors: CL
authors: Hall
authors: Nallasivam
authors: N
authors: Palanisamy
authors: Amber N
authors: AN
authors: Heath
authors: Nader
authors: N
authors: Tawakkol
authors: Tahra K
authors: TK
authors: Luther
authors: Shawn G
authors: SG
authors: Clouthier
authors: Whitney A
authors: WA
authors: Chadwick
authors: Mark L
authors: ML
authors: Day
authors: Celina G
authors: CG
authors: Kleer
authors: Dafydd G
authors: DG
authors: Thomas
authors: Daniel F
authors: DF
authors: Hayes
authors: Hasan
authors: H
authors: Korkaya
authors: Max S
authors: MS
authors: Wicha
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D015415:Biomarkers; D001859:Bone Neoplasms / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D014183:Transplantation, Heterologous; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D011960:Receptors, Estrogen; D000068878:Trastuzumab