Original studyAldehyde Dehydrogenase 1 Expression in Inflammatory Breast Cancer as Measured by Immunohistochemical Staining
Introduction
Inflammatory breast cancer (IBC) is a rare but aggressive type of breast cancer.1 It is characterized clinically by early metastasis and inflammatory-appearing changes of the breast owing to florid lymphovascular invasion of the tumor emboli. Despite multimodality treatment approaches, the clinical outcome of patients with IBC remains poor, with an overall survival (OS) rate of 35% to 40%, which is much lower than that of patients with non-IBC breast cancer.1, 2, 3 Gaining biologic insights into IBC and identifying suitable therapeutic targets are highly desirable.
The cancer stem cell (CSC) concept proposes that cancers arise from a small percentage of tumor cells that possess properties of self-renewal, high proliferation potential, multilineage differentiation, and tumorigenicity. Mounting evidence has indicated that CSCs exist in breast cancer, that they are responsible for tumor resistance to conventional chemotherapy and radiotherapy and for recurrence/metastasis, and that they are more frequently seen in aggressive carcinoma.4, 5, 6
Several putative CSC markers have been evaluated in both preclinical and clinical studies, among which aldehyde dehydrogenase 1 (ALDH1) positivity and the CD44-positive/CD24-negative (CD44+/CD24−) phenotype are the 2 most commonly used.4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ALDH1 is a detoxifying enzyme responsible for oxidizing intracellular aldehydes to carboxylic acids. ALDH1 has a role in the conversion of retinol (vitamin A) to retinoic acid, which is important for proliferation, differentiation, and survival.4, 7, 16 Interestingly, there is no significant correlation between ALDH1+ cells and CD44+/CD24− cells within the same breast cancer samples, and the overlap between the 2 populations is poor.4, 8, 9, 11, 17 Several studies have suggested that ALDH1 is a better CSC marker than the CD44+/CD24− phenotype. For example, Ginestier et al4 reported that ALDH1-expressing tumor cells are more tumorigenic than CD44+/CD24− tumor cells in immunodeficient mice. In addition, ALDH1 is also involved in metabolizing chemotherapeutic drugs. Significant resistance to sequential paclitaxel- and epirubicin-based chemotherapy was found in tumor cells expressing ALDH1, but not in cells with the CD44+/CD24− phenotype.11 A higher ALDH1 level was associated with lower frequency of clinical response to cyclophosphamide-based chemotherapy.18 Inhibition of ALDH1 activity reduces chemotherapy and radiation resistance in stem-like human breast cancer cell lines.19 Compared with CD44/CD24 testing, ALDH1 expression can be more readily examined using immunohistochemical (IHC) staining, which is amenable to archival formalin-fixed, paraffin-embedded tissues.4, 8, 10, 11, 17, 20, 21, 22, 23, 24, 25, 26, 27
To date, little is known about the role of CSCs in the biologic behaviors of IBC tumors. In 2008, stem cell signaling pathways such as Notch3 were found to be active in a human IBC xenograft (MARY-X); MARY-X spheroids frequently expressed CD44+/CD24−, ALDH1, and other CSC phenotypes.28 When testing human IBC samples, they found ALDH1 expression in 10% to 100% of tumor cells within lymphovascular emboli, suggesting that the stem cell–like phenotype may contribute to the aggressive nature of IBC. Charafe-Jauffret et al8 reported that ALDH1+ cells mediated invasive and metastatic behavior in both IBC cell line (SUM 149) and xenograft (MARY-X) assays. Moreover, the ALDH1+ phenotype, but not the CD44+/CD24− phenotype, was an independent marker in predicting metastasis in patients with IBC.
If ALDH1 expression is proven to be associated with aggressive clinicopathologic parameters of IBC, therapeutic strategies aimed at targeting ALDH1-expressing cells may be beneficial for these patients. The purpose of the present study was to evaluate ALDH1 expression, using IHC staining, in a cohort of IBC tumors collected at the authors' institution. The results were correlated with clinicopathologic parameters and survival data and were compared with data published in the literature.
Section snippets
Patients
A total of 74 patients with primary IBC who were treated at the University of Texas MD Anderson Cancer Center from September 1994 to August 2004 with available tumor tissue and clinical follow-up information were included. The diagnosis, preoperative treatment, and postoperative treatment of these patients have been reported previously,29 as well as information on biomarker studies (encompassing estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2
Results
Of the 74 patients included in this study, 59 (80%) were white, 10 (14%) were Hispanic, and 5 (7%) were black or Asian. The ages of the patients ranged from 23 to 75 years (median, 49 years). Fifty-four patients had stage IIIb tumors, 11 had stage IIIc, and 8 had stage IV. Lymph node involvement was found in 64 patients (86%). Histologically, 66 tumors (89%) were ductal type, 58 tumors (78%) were high grade, and 60 tumors (81%) demonstrated lymphovascular invasion (Table 1).
Of the 74 tumors, ER
Discussion
ALDH1 expression in breast cancer was originally tested using the Aldefluor flow cytometry–based assay. In 2007, Ginestier et al4 first found that immunohistochemically identified ALDH1 expression was associated with poor clinical outcome in human breast cancer. In that study, 2 separate breast cancer cohorts (136 patients in an American cohort and 345 patients in a French cohort) were analyzed, and ALDH1 positivity was found in 19% and 30% of the patients, respectively. The 5-year OS rates for
Conclusion
In the present study, a significant correlation between ALDH1 expression and prognosis or other clinicopathologic variables in an IBC cohort was not observed. The presence of substantial inconsistency in ALDH1 expression and its clinical/pathologic relevance reported in the literature highlights uncertainties, both theoretical and technical, about the reliability of immunohistochemically identified ALDH1 as a sole marker for CSCs of breast carcinoma. Further studies with large series are
Acknowledgments
The authors thank Sunita Patterson of the Department of Scientific Publications at the University of Texas MD Anderson Cancer Center for editing the manuscript.
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