Purpose: Breast cancer stem cells have been shown to be associated with resistance to chemotherapy in vitro, but their clinical significance remains to be clarified. The aim of this study was to investigate whether cancer stem cells were clinically significant for resistance to chemotherapy in human breast cancers. Experimental Design: Primary breast cancer patients (n = 108) treated with neoadjuvant chemotherapy consisting of sequential paclitaxel and epirubicin-based chemotherapy were included in the study. Breast cancer stem cells were identified by immunohistochemical staining of CD44/CD24 and aldehyde dehydrogenase 1 (ALDH1) in tumor tissues obtained before and after neoadjuvant chemotherapy. CD44 + /CD24-tumor cells or ALDH1-positive tumor cells were considered stem cells. Results: Thirty (27.8%) patients achieved pathologic complete response (pCR). ALDH1-positive tumors were significantly associated with a low pCR rate (9.5% versus 32.2%; P = 0.037), but there was no significant association between CD44 + /CD24 -tumor cell proportions and pCR rates. Changes in the proportion of CD44 + /CD24 -or ALDH1-positive tumor cells before and after neoadjuvant chemotherapy were studied in 78 patients who did not achieve pCR. The proportion of ALDH1-positive tumor cells increased significantly (P < 0.001) after neoadjuvant chemotherapy, but that of CD44 + /CD24 -tumor cells did not. Conclusions: Our findings suggest that breast cancer stem cells identified as ALDH1-positive, but not CD44

Recently, aldehyde dehydrogenase (ALDH) 1 has been identified as a reliable marker for breast cancer stem cells. E vidence has recently been accumulating to support the cancer stem cell hypothesis for solid tumors, including breast cancer, which holds that cancers are driven by a small subpopulation of stem cells that are capable of self-renewal and give rise to multipotent progenitor cells that ultimately differentiate into all cell types within the tumor.(1) Al-Hajj et al. were the first to distinguish tumorigenic from non-tumorigenic cancer cells by using the cell surface markers CD44 and CD24.(2) They have shown that cancer stem cells in a population of tumor cells are enriched with the CD44 + and CD24 -phenotype because as few as 100 tumor cells with this phenotype were able to produce tumors in immunodeficient mice, whereas tumor cells with other CD44 and CD24 phenotypes were unable or rarely able to produce tumors even when as many as 10 5 -10 6 tumor cells were inoculated into such mice. + cancer stem cells may well be clinically useful for patient prognosis. In the study reported here, we therefore investigated the clinicopathological characteristics of breast cancers with ALDH1 + cancer stem cells and also compared ALDH1 expression in primary tumors and axillary metastases. In addition, the ER, Ki67, and HER2 status of ALDH1 + tumor cells was investigated on a cell-by-cell basis by means of double immunohistochemical staining for further characterization of the phenotype of breast cancer stem cells. Materials and MethodsPatients and breast tumor tissues. Tumor tissue samples were obtained from 203 primary breast cancer patients (mean age, 52.6 years; range, 32-86 years) who underwent mastectomy or breast-conserving surgery between January 1993 and December 1997 at Osaka University Hospital, Osaka, Japan. Tumor tissues were fixed in 10% buffered formalin and embedded in paraffin. This study protocol was approved by the Ethics Committee of Osaka University.For adjuvant therapy, 85 patients were treated with hormonal therapy (tamoxifen, n = 74; toremifene, n = 7; gosereline, n = 3; or gosereline + tamoxifen, n = 1), 22 with chemotherapy (fluoropyrimidine, n = 8; cyclophosphamide + methotrexate + 5-fluorouracil, n = 7; cyclophosphamide + adriamycin + 5-fluorouracil, n = 4; or high-dose chemotherapy, n = 3), and 84 with chemohormonal therapy (fluoropyrimidine, n = 37; cyclophosphamide + methotrexate + 5-fluorouracil, n = 25; cyclophosphamide + adriamycin + 5-fluorouracil, n = 20; or high-dose chemotherapy, n = 2; plus tamoxifen, n = 78; toremifene, n = 1; gosereline, n = 3; or gosereline + tamoxifen, n = 2). Twelve patients received no adjuvant therapy.

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