Insulin growth factor receptor-1 expression and loss of PTEN protein predict early recurrence in triple-negative breast cancer Jabed Iqbal, Aye Aye Thike, Poh Yian Cheok, Gary Man-Kit Tse 1 & Puay Hoon Tan Department of Pathology, Singapore General Hospital, Singapore, and 1 Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China Date of submission 16 August 2011 Accepted for publication 21 December 2011 Iqbal J, Thike A A, Cheok P Y, Tse G M-K & Tan P H (2012) Histopathology Insulin growth factor receptor-1 expression and loss of PTEN protein predict early recurrence in triple-negative breast cancer Aims: Insulin-like growth factor receptor-1 (IGFR-1) and its signalling axis promote tumorigenesis, metas- tasis, and resistance to existing forms of cancer therapy, and have become a major focus for the development of anticancer drugs. As oncological man- agement options for triple-negative breast cancers (TNBCs) are limited, there is potential for the rapid development of novel selective anticancer agents spe- cifically targeting components of the PTEN–phospho- inositide 3-kinase–AKT pathway, including the phosphorylated form of AKT (pAKT) and the tumour suppressor molecule PTEN. The aim of this study was to conduct immunohistochemical analyses to examine the levels of PTEN, IGFR-1 and pAKT expression in TNBCs, and determine whether these levels correlated with poor prognosis in this subset of aggressive breast cancers. Methods and results: Immunohistochemistry was per- formed on paraffin-embedded tumour tissues from a consecutive cohort of 144 female patients diagnosed with TNBC. Associations of IGFR-1, PTEN and pAKT expression with clinicopathological parameters, dis- ease-free survival (DFS) and overall survival (OS) were evaluated. There were significant increases in IGFR-1 expression (99%) and pAKT expression (92%) with concomitant loss of PTEN expression in the majority of cases (63%). Increased IGFR-1 expression and loss of PTEN expression were associated with reduced OS and DFS, respectively. pAKT expression showed a strong correlation with basal-like expression. Combinatorial immunophenotypic analyses showed that loss of PTEN expression with concomitant IGFR-1 expression corre- lated with poor DFS. Conclusions:A high percentage of PTEN loss with overexpression of IGFR-1 and pAKT in TNBC indicates the potential of these molecules for predicting early recurrence and ⁄ or as targets in the formulation of effective alternative therapy regimens. Keywords: basal-like, IGFR-1, pAKT, PTEN, targeted treatment, triple-negative Abbreviations: BLC, basal-like breast carcinoma; CK, cytokeratin; DCIS, ductal carcinoma in situ; DFS, disease-free survival; EGFR, epidermal growth factor receptor; ER, oestrogen receptor; IGF, insulin-like growth factor; IGFR-1, insulin-like growth factor receptor-1; mAb, monoclonal antibody; mTOR, mammalian target of rapamycin; OS, overall survival; pAKT, phosphorylated AKT; PI3K, phosphoinositide 3-kinase; PR, progesterone receptor; RTK, receptor tyrosine kinase; TMA, tissue microarray; TNBC, triple-negative breast cancer Introduction Insulin-like growth factor receptor-1 (IGFR-1) is a transmembrane heterotetrameric protein, encoded by the IGFR-1 gene located on chromosome 15q25–q26, that promotes oncogenic transformation, growth and survival of cancer cells. 1–8 The binding of insulin-like growth factor (IGF)-I and IGF-II to the extracellular Address for correspondence: Dr P H Tan, Department of Pathology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore. e-mail: tan.puay.hoon@sgh.com.sg Ó 2012 Blackwell Publishing Limited. Histopathology 2012 DOI: 10.1111/j.1365-2559.2012.04255.x