PAR-4 – a novel marker of luminal A breast cancer – is down-regulated by the steroid receptor co-activator SRC-1

Abstract

Introduction: Prostate apoptosis response-4 (PAR-4, PAW-R, PKC apoptosis WT1 regulator) is a gene coding for a tumour suppressor protein involved in the selective apoptosis of cancer cells. Although well described in renal cell carcinomas and prostate cancer, little is known about its role and regulation in breast cancer. Methods: Western blotting techniques looked at the association between PAR-4 expression and breast cancer sub-type, and at the effects of steroid receptor co-activator-1 (SRC-1) on PAR-4 expression. Functional assays (3D cell culture and adhesion independent growth) investigated the role of PAR-4 in breast cancer cells and immunohistochemistry looked at the clinical correlations of PAR-4 positivity in our patient cohort. Results: The results show that PAR-4 is down-regulated by SRC-1 in endocrine-resistant cell lines and they validate its use as a marker of good disease-free survival, both in vitro and in vivo. In addition, the functional assays provide evidence that PAR-4 may play a role in maintaining a well-differentiated phenotype in breast cancer cell lines. Conclusion: The results suggest that PAR-4 expression is a marker of good disease-free survival, or conversely, that the loss of PAR-4 expression would signal tumour progression to a more aggressive phenotype. The identification of such markers is important in the development of more personalised forms of treatments.</p