TY - JOUR
T1 - HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification
T2 - Implications for efficacy of
AU - Trastuzumab, Adjuvant
AU - Ithimakin, Suthinee
AU - Day, Kathleen C.
AU - Malik, Fayaz
AU - Zen, Qin
AU - Dawsey, Scott J.
AU - Bersano-Begey, Tom F.
AU - Quraishi, Ahmed A.
AU - Ignatoski, Kathleen Woods
AU - Daignault, Stephanie
AU - Davis, April
AU - Hall, Christopher L.
AU - Palanisamy, Nallasivam
AU - Heath, Amber N.
AU - Tawakkol, Nader
AU - Luther, Tahra K.
AU - Clouthier, Shawn G.
AU - Chadwick, Whitney A.
AU - Day, Mark L.
AU - Kleer, Celina G.
AU - Thomas, Dafydd G.
AU - Hayes, Daniel F.
AU - Korkaya, Hasan
AU - Wicha, Max S.
PY - 2013/3/1
Y1 - 2013/3/1
N2 - 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-kB (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.
AB - 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-kB (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.
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U2 - 10.1158/0008-5472.CAN-12-3349
DO - 10.1158/0008-5472.CAN-12-3349
M3 - Article
C2 - 23442322
AN - SCOPUS:84874857331
SN - 0008-5472
VL - 73
SP - 1635
EP - 1646
JO - Cancer Research
JF - Cancer Research
IS - 5
ER -