Aldehyde dehydrogenase 1 expression is a predictor of poor prognosis in node-positive breast cancers: a long-term follow-up study Takako Yoshioka, Yoshihisa Umekita, Yasuyo Ohi, 1 Masakazu Souda, Yoshiatsu Sagara, 1 Yasuaki Sagara, 1 Yoshiaki Sagara, 1 Yoshiaki Rai 1 & Akihide Tanimoto Department of Molecular and Cellular Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, and 1 Hakuaikai Sagara Hospital, Kagoshima, Japan Date of submission 27 January 2010 Accepted for publication 25 May 2010 Yoshioka T, Umekita Y, Ohi Y, Souda M, Sagara Y, Sagara Y, Sagara Y, Rai Y & Tanimoto A (2011) Histopathology 58, 608–616 Aldehyde dehydrogenase 1 expression is a predictor of poor prognosis in node-positive breast cancers: a long-term follow-up study Aims: Aldehyde dehydrogenase 1 (ALDH1) has been identified as a reliable marker of breast cancer stem cells. The aim was to determine the prognostic signif- icance of ALDH1 expression in a long-term follow-up study. Methods and results: Immunohistochemical analyses were performed on 257 invasive ductal carcinomas (IDCs), 109 matched lymph node metastases and 190 ductal carcinomas in situ (DCISs), using paraffin- embedded sections. ALDH1 expression was found in 26% of IDCs, and correlated with larger tumour size (P = 0.007), high histological grade (P < 0.001), HER2 overexpression (P < 0.001) and negative hor- mone receptor status (P < 0.001). ALDH1 expression was observed in 14% of DCISs but was not correlated with any clinicopathological parameter. The IDC patients were followed up for 7–190 months (median: 120 months), and groups with ALDH1 expression had shorter relapse-free survival (P = 0.0013) and overall survival (OS) (P = 0.0005) by log-rank test. By Cox’s multivariate analysis, it had a weak effect on OS (P = 0.047), and its most significant effect on OS was observed in node-positive groups (P = 0.013). No significant differences in OS stratified by ALDH1 expression status in lymph node metastases were noted. Conclusions: ALDH1 expression in primary cancer is an independent prognostic factor in node-positive breast cancer patients. Keywords: ALDH1, breast cancer, immunohistochemistry Abbreviations: ALDH1, aldehyde dehydrogenase 1; CI, confidence interval; DCIS, ductal carcinoma in situ; ER, oestrogen receptor; IDC, invasive ductal carcinoma; OS, overall survival; PgR, progesterone receptor; RFS, relapse-free survival; TMA, tissue microarray; WHO, World Health Organization Introduction The cancer stem cell hypothesis is a new paradigm that could have a major impact on the treatment of disease by suggesting a new target for cancer therapy, in addition to having clinical implications for early detection and prognostication. Cancer stem cells were first identified in leukaemia, 1 and have more recently been identified in solid tumours, including breast cancers. 2 A promising new marker of cancer stem cells is aldehyde dehydrogenase 1 (ALDH1). ALDH1 is a detoxifying enzyme that oxidizes intracellular aldehydes and thereby confers resistance on alkylating agents. 3,4 In fact, the detoxification capacity of ALDH, by protecting stem cells against oxidative insult, might underlie the well-recognized longevity of stem cells. ALDH1 also converts retinol to retinoic acid, Address for correspondence: A Tanimoto, MD, PhD, Department of Molecular and Cellular Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan. e-mail: akit09@m3.kufm.kagoshima-u.ac.jp T.Y. and Y.U. contributed equally to this work. Ó 2011 Blackwell Publishing Limited. Histopathology 2011, 58, 608–616. DOI: 10.1111/j.1365-2559.2011.03781.x