HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification

Implications for efficacy of

Adjuvant Trastuzumab, Suthinee Ithimakin, Kathleen C. Day, Fayaz Malik, Qin Zen, Scott J. Dawsey, Tom F. Bersano-Begey, Ahmed A. Quraishi, Kathleen Woods Ignatoski, Stephanie Daignault, April Davis, Christopher L. Hall, Nallasivam Palanisamy, Amber N. Heath, Nader Tawakkol, Tahra K. Luther, Shawn G. Clouthier, Whitney A. Chadwick, Mark L. Day, Celina G. Kleer & 4 others Dafydd G. Thomas, Daniel F. Hayes, Hasan Korkaya, Max S. Wicha

Research output: Contribution to journalArticle

147 Citations (Scopus)

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-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.

Original languageEnglish (US)
Pages (from-to)1635-1646
Number of pages12
JournalCancer Research
Volume73
Issue number5
DOIs
StatePublished - Mar 1 2013

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Neoplastic Stem Cells
Gene Amplification
Breast Neoplasms
Heterografts
erbB-2 Genes
Neoplasms
Bone and Bones
NF-kappa B
Growth
Estrogen Receptors
Population
Guidelines
Neoplasm Metastasis
Ligands
Cell Line
Therapeutics
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Trastuzumab, A., Ithimakin, S., Day, K. C., Malik, F., Zen, Q., Dawsey, S. J., ... Wicha, M. S. (2013). HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: Implications for efficacy of. Cancer Research, 73(5), 1635-1646. https://doi.org/10.1158/0008-5472.CAN-12-3349

HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification : Implications for efficacy of. / Trastuzumab, Adjuvant; 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.

In: Cancer Research, Vol. 73, No. 5, 01.03.2013, p. 1635-1646.

Research output: Contribution to journalArticle

Trastuzumab, A, Ithimakin, S, Day, KC, Malik, F, Zen, Q, Dawsey, SJ, Bersano-Begey, TF, Quraishi, AA, Ignatoski, KW, Daignault, S, Davis, A, Hall, CL, Palanisamy, N, Heath, AN, Tawakkol, N, Luther, TK, Clouthier, SG, Chadwick, WA, Day, ML, Kleer, CG, Thomas, DG, Hayes, DF, Korkaya, H & Wicha, MS 2013, 'HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: Implications for efficacy of', Cancer Research, vol. 73, no. 5, pp. 1635-1646. https://doi.org/10.1158/0008-5472.CAN-12-3349
Trastuzumab, Adjuvant ; 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. / HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification : Implications for efficacy of. In: Cancer Research. 2013 ; Vol. 73, No. 5. pp. 1635-1646.
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