HER2 Drives Luminal Breast Cancer Stem Cells in the Absence of HER2 Amplification: Implications for Efficacy of Adjuvant Trastuzumab

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 5; pp. 1635 - 1646
• Main Authors: Ithimakin, Suthinee, Day, Kathleen C., Malik, Fayaz, Zen, Qin, Dawsey, Scott J., Bersano-Begey, Tom F., Quraishi, Ahmed A., Ignatoski, Kathleen Woods, Daignault, Stephanie, Davis, April, Hall, Christopher L., Palanisamy, Nallasivam, Heath, Amber N., Tawakkol, Nader, Luther, Tahra K., Clouthier, Shawn G., Chadwick, Whitney A., Day, Mark L., Kleer, Celina G., Thomas, Dafydd G., Hayes, Daniel F., Korkaya, Hasan, Wicha, Max S.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.03.2013
• Subjects: Animals; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic agents; Biological and medical sciences; Biomarkers; Bone Neoplasms - secondary; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Female; Gene Amplification; Genes, erbB-2; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Mice; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Transplantation; Neoplastic Stem Cells - metabolism; Pharmacology. Drug treatments; Receptors, Estrogen - metabolism; Transplantation, Heterologous; Trastuzumab; Tumors; Antineoplastic agent; Breast disease; Stem cell; Treatment efficiency; erbB2 Gene; Breast cancer; Monoclonal antibody; Malignant tumor; Human Epidermal growth factor Receptor 2; Mammary gland diseases; Gene amplification; C-Onc gene; Tumor cell; Protooncogene; Trastuzumab; Cancer
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-12-3349

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.