High Expression of <scp>PAPP</scp> ‐A Predicts Poor Outcomes in Oestrogen Receptor‐Positive Breast Cancer Patients

INTRODUCTION: Insulin-like growth factor 1 (IGF-1)/IGF-1 receptor (IGF-1R) signalling is activated in breast cancer and associated with disease progression. Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase that can cleave IGF binding proteins leading to the release of bioactive IGF-1 and the subsequent activation of IGF-1 signalling. Here, we aimed to assess the prognostic significance of PAPP-A in breast cancer. METHODS: Breast cancer tissue microarrays were stained for PAPP-A and expression correlated with survival and other clinical features. Analysis of publicly available data sets was carried out to determine associations between PAPPA and gene sets associated with IGF-1/IGF-1R pathway activation. RESULTS: PAPP-A was expressed in both the tumour and stromal compartments in breast cancer specimens and was higher in oestrogen receptor (ER)-negative (ER-) than ER-positive (ER+) cases. There was a significant association between high PAPP-A expression and reduced cancer-specific survival (CSS) in ER+ (HR 1.389, 95% CI 1.051-1.836, p = 0.021) but not ER- patients (HR 1.040, 95% CI 0.712-1.598, p = 0.838). In a second cohort of ER+ invasive lobular carcinoma (ILC) PAPP-A expression was also associated with reduced CSS (HR 1.765, 95% CI 1.098-2.836, p = 0.019). PAPPA correlated with REACTOME PI3K-AKT and IGF1R signalling gene sets in ER+ breast cancers. CONCLUSION: High expression of PAPP-A is associated with poor prognosis in ER+ breast cancer and correlates with IGF-1/IGF-1R pathway activation.