Am J Cancer Res 2013;3(2):211-220
Original Article
Targeting breast cancer stem cells with HER2-specific antibodies and natural
killer cells
Joachim Diessner, Valentin Bruttel, Kathrin Becker, Miriam Pawlik, Roland Stein, Sebastian Häusler, Johannes Dietl, Jörg
Wischhu-sen, Arnd Hönig
Junior research group “tumor progression and immune escape”, Interdisciplinary Center for Clinical Research (IZKF);
Department for Obstet-rics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Str. 4, 97080 Würzburg,
Germany. These authors contributed equally.
Received March 13, 2013; Accepted March 28, 2013; Epub April 3, 2013; Published April 13, 2013
Abstract: Breast cancer is the most common cancer among women worldwide. Every year, nearly 1.4 million new cases of
breast cancer are diagnosed, and about 450.000 women die of the disease. Approximately 15-25% of breast cancer cases
exhibit increased quantities of the trans-membrane receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2)
on the tumor cell surface. Previous studies showed that blockade of this HER2 proto-oncogene with the antibody trastuzumab
substantially improved the overall survival of patients with this aggressive type of breast cancer. Recruitment of natural killer (NK)
cells and subsequent induction of antibody-dependent cell-mediated cytotoxicity (ADCC) contributed to this beneficial effect. We
hypothesized that antibody binding to HER2-positive breast cancer cells and thus ADCC might be further improved by
synergistically applying two different HER2-specific antibodies, trastuzumab and pertuzumab. We found that tumor cell killing via
ADCC was increased when the combination of trastuzumab, pertuzumab, and NK cells was applied to HER2-positive breast
cancer cells, as compared to the extent of ADCC induced by a single antibody. Furthermore, a subset of
CD44highCD24lowHER2low cells, which possessed characteristics of cancer stem cells, could be targeted more efficiently by
the combination of two HER2-specific antibodies compared to the efficiency of one antibody. These in vitro results demonstrated
the immunotherapeutic benefit achieved by the combined application of trastuzumab and pertuzumab. These findings are
consistent with the positive results of the clinical studies, CLEOPATRA and NEOSPHERE, conducted with patients that had
HER2-positive breast cancer. Compared to a single antibody treatment, the combined application of trastuzumab and
pertuzumab showed a stronger ADCC effect and improved the targeting of breast cancer stem cells. (AJCR0000187)
Keywords: Trastuzumab, pertuzumab, ADCC, tumor stem cells, breast cancer
Address correspondence to: Dr. Arnd Hönig, University of Wuerzburg, Josef-Schneider Str. 4, 97080 Würzburg, Germany. Tel:
+49 (0) 1799443540, +49 (0) 931-201-25253; Fax: +49 (0) 931-201-25406; E-mail: arnd_hoenig@hotmail.com
Original Article
Targeting breast cancer stem cells with HER2-specific antibodies and natural
killer cells
Joachim Diessner, Valentin Bruttel, Kathrin Becker, Miriam Pawlik, Roland Stein, Sebastian Häusler, Johannes Dietl, Jörg
Wischhu-sen, Arnd Hönig
Junior research group “tumor progression and immune escape”, Interdisciplinary Center for Clinical Research (IZKF);
Department for Obstet-rics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Str. 4, 97080 Würzburg,
Germany. These authors contributed equally.
Received March 13, 2013; Accepted March 28, 2013; Epub April 3, 2013; Published April 13, 2013
Abstract: Breast cancer is the most common cancer among women worldwide. Every year, nearly 1.4 million new cases of
breast cancer are diagnosed, and about 450.000 women die of the disease. Approximately 15-25% of breast cancer cases
exhibit increased quantities of the trans-membrane receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2)
on the tumor cell surface. Previous studies showed that blockade of this HER2 proto-oncogene with the antibody trastuzumab
substantially improved the overall survival of patients with this aggressive type of breast cancer. Recruitment of natural killer (NK)
cells and subsequent induction of antibody-dependent cell-mediated cytotoxicity (ADCC) contributed to this beneficial effect. We
hypothesized that antibody binding to HER2-positive breast cancer cells and thus ADCC might be further improved by
synergistically applying two different HER2-specific antibodies, trastuzumab and pertuzumab. We found that tumor cell killing via
ADCC was increased when the combination of trastuzumab, pertuzumab, and NK cells was applied to HER2-positive breast
cancer cells, as compared to the extent of ADCC induced by a single antibody. Furthermore, a subset of
CD44highCD24lowHER2low cells, which possessed characteristics of cancer stem cells, could be targeted more efficiently by
the combination of two HER2-specific antibodies compared to the efficiency of one antibody. These in vitro results demonstrated
the immunotherapeutic benefit achieved by the combined application of trastuzumab and pertuzumab. These findings are
consistent with the positive results of the clinical studies, CLEOPATRA and NEOSPHERE, conducted with patients that had
HER2-positive breast cancer. Compared to a single antibody treatment, the combined application of trastuzumab and
pertuzumab showed a stronger ADCC effect and improved the targeting of breast cancer stem cells. (AJCR0000187)
Keywords: Trastuzumab, pertuzumab, ADCC, tumor stem cells, breast cancer
Address correspondence to: Dr. Arnd Hönig, University of Wuerzburg, Josef-Schneider Str. 4, 97080 Würzburg, Germany. Tel:
+49 (0) 1799443540, +49 (0) 931-201-25253; Fax: +49 (0) 931-201-25406; E-mail: arnd_hoenig@hotmail.com
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American Journal of Cancer Research
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