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Old 06-11-2009, 04:14 PM   #15
Rich66
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1: J Natl Cancer Inst. 2008 May 7;100(9):672-9. Epub 2008 Apr 29. Links
Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy.

Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC, Wong H, Rosen J, Chang JC.
Breast Center at Baylor College of Medicine, 1 Baylor Plaza BCM 600, TX 77030, USA.
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 statistically non-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.
PMID: 18445819 [PubMed - indexed for MEDLINE]

News
What are the clinical implications of breast-cancer stem cells?


Kathryn Senior





PII S1470-2045(08)70141-4
DOI 10.1016/S1470-2045(08)70141-4


The number of breast-cancer stem cells expressing the CD44+/CD24-/low marker decreased in women with primary breast cancer after treatment with lapatinib, reported researchers at the 6th European Breast Cancer Conference (Berlin, Germany; April 15–19, 2008).
“The activity of lapatinib, an epidermal growth factor receptor (EGFR)/ERBB2 tyrosine-kinase inhibitor, suggests that targeting specific signalling pathways responsible for self renewal of these cells could provide a therapeutic strategy for eliminating breast-cancer stem cells”, says Jenny Chang (Baylor College of Medicine, Houston, TX, USA) co-author on the lapatinib study. Max Wicha (University of Michigan, Ann Arbor, MI, USA) agrees: “this is consistent with our findings that ERBB2 is an important regulator of the breast-cancer stem-cell phenotype”…
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