Journal of the National Cancer Institute Advance Access originally published online on April 29, 2008
JNCI Journal of the National Cancer Institute 2008 100(9):672-679; doi:10.1093/jnci/djn123
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ARTICLES |
Intrinsic Resistance of Tumorigenic Breast Cancer Cells to Chemotherapy
Affiliations of authors: Breast Center, Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Division of Biostatistics and Department of Surgery, Baylor College of Medicine, Houston, TX 77030
Correspondence to: Jenny C. Chang, MD, Breast Center at Baylor College of Medicine, 1 Baylor Plaza BCM 600, TX 77030 (e-mail: jcchang{at}bcm.edu).
Background: Tumorigenic breast cancer cells that express high levels of CD44 and low or undetectable levels of CD24 (CD44>/CD24>/low) may be resistant to chemotherapy and therefore responsible for cancer relapse. These tumorigenic cancer cells can be isolated from breast cancer biopsies and propagated as mammospheres in vitro. In this study, we aimed to test directly in human breast cancers the effect of conventional chemotherapy or lapatinib (an epidermal growth factor receptor [EGFR]/HER2 pathway inhibitor) on this tumorigenic CD44> and CD24>/low cell population.
Methods: Paired breast cancer core biopsies were obtained from patients with primary breast cancer before and after 12 weeks of treatment with neoadjuvant chemotherapy (n = 31) or, for patients with HER2-positive tumors, before and after 6 weeks of treatment with the EGFR/HER2 inhibitor lapatinib (n = 21). Single-cell suspensions established from these biopsies were stained with antibodies against CD24, CD44, and lineage markers and analyzed by flow cytometry. The potential of cells from biopsy samples taken before and after treatment to form mammospheres in culture was compared. All statistical tests were two-sided.
Results: Chemotherapy treatment increased the percentage of CD44>/CD24>/low cells (mean at baseline vs 12 weeks, 4.7%, 95% confidence interval [CI] = 3.5% to 5.9%, vs 13.6%, 95% CI = 10.9% to 16.3%; P < .001) and increased mammosphere formation efficiency (MSFE) (mean at baseline vs 12 weeks, 13.3%, 95% CI = 6.0% to 20.6%, vs 53.2%, 95% CI = 42.4% to 64.0%; P < .001). Conversely, lapatinib treatment of patients with HER2-positive tumors led to a non–statistically significant decrease in the percentage of CD44>/CD24>/low cells (mean at baseline vs 6 weeks, 10.0%, 95% CI = 7.2% to 12.8%, vs 7.5%, 95% CI = 4.1% to 10.9%) and a non–statistically significant decrease in MSFE (mean at baseline vs 6 weeks, 16.1%, 95% CI = 8.7% to 23.5%, vs 10.8%, 95% CI = 4.0% to 17.6%).
Conclusion: These studies provide clinical evidence for a subpopulation of chemotherapy-resistant breast cancer–initiating cells. Lapatinib did not lead to an increase in these tumorigenic cells, and, in combination with conventional therapy, specific pathway inhibitors may provide a therapeutic strategy for eliminating these cells to decrease recurrence and improve long-term survival.
| CONTEXT AND CAVEATS Prior knowledge Breast cancer cells that express high levels of CD44 and low levels of CD24 (CD44>/CD24>/low) may be responsible for tumor recurrence. HER2-positive cancers may have increased self-renewal properties. Study design Breast cancer patients were treated with neoadjuvant chemotherapy (HER2-negative patients) or the epidermal growth factor receptor/HER2 inhibitor lapatinib (HER2-positive patients). Cells that were isolated from biopsy samples taken before and after therapy were assayed for the percentage of CD44>/CD24>/low cells and the ability to form mammospheres in vivo as an indication of self-renewal. Contributions Treatment with chemotherapy increased the percentage of CD44>/CD24>/low cells and the formation of mammospheres, whereas treatment with lapatinib non–statistically significantly reduced the percentage of CD44>/CD24>/low cells and the formation of mammospheres. Implications Tumorigenic CD44>/CD24>/low cells may be chemotherapy resistant. Lapatinib treatment did not increase the proportion of these tumorigenic cells in HER2-positive breast cancers. Limitations Breast cancers and samples taken from them contain several different cell types; thus, it is difficult to distinguish the roles of each cell type and those of cell–cell interactions in the effects observed. CD44>/CD24>/low cells have been shown to have high tumorigenic potential and to be resistant to chemotherapy and radiation therapy, but their role in metastasis is still unclear.
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The two first authors (X. Li and M. T. Lewis) and two senior authors (J. Rosen and J. C. Chang) contributed equally to this study. The sponsors had no role in the study design, data collection and analysis, interpretation of the results, the preparation of the manuscript, or the decision to submit the manuscript for publication.
Manuscript received November 2, 2007; revised February 18, 2008; accepted March 18, 2008.
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