Lack of expression of the proteins GMPR2 and PPARα are associated with the basal phenotype and patient outcome in breast cancer

Basal-like tumours (BP) are a poor prognostic class of breast cancer but remain a biologically and clinically heterogeneous group. We have previously identified two novel genes PPAR alpha (positive) and GMPR2 (negative) whose expression was significantly associated with BP at the transcriptome level. In this study, using a large and well-characterised series of operable invasive breast carcinomas (1,043 cases) prepared as TMAs, we assessed these targets at the protein level using immunohistochemistry and investigated associations with clinicopathological variables and patient outcome. Results: Lack of PPAR alpha and GMPR2 protein expression was associated with BP, as defined by the expression of cytokeratin (CK) 5/6 and/or CK14, (p = 0.023, p = 0.001, respectively) or as triple-negative (ER-, PR-, HER2-) phenotype (p < 0.001 for both proteins). Positive expression of both markers was associated ER and PR positive status (p < 0.05) and with the good Nottingham Prognostic Index group (p = 0.012, p < 0.001, respectively). Univariate survival analysis showed an association between lack of expression of PPAR alpha and GMPR2 and poor outcome in terms of shorter disease-free survival and shorter breastcancer-specific survival, respectively. However, multivariate analysis showed that these associations were not independent of other prognostic variables, namely tumour size, grade, and nodal stage. In conclusion, this study demonstrates that loss of expression of GMPR2 and PPAR alpha is associated with BP at the protein level; indicating that they may play a role in carcinogenesis of this molecularly complex and clinically important subtype. Further studies into their relevance in further classification of BP are warranted.