Aberrant pregnancy-associated plasma protein-A expression in breast cancers prognosticates clinical outcomes

Prashanth Prithviraj,Matthew Anaka,Aparna Jayachandran,Erik W Thompson,Candani S A Tutuka,Revati Sharma,Marzena Walkiewicz,George Kannourakis,Andreas Behren

doi:10.1038/s41598-020-70774-9

Abstract

Elevated levels of pregnancy-associated plasma protein-A (PAPP-A) have been implicated in the pathogenesis of various malignancies, including breast cancers. Breast cancer is one of the most frequent carcinomas and is the second most common cancer type detected in women of child-bearing age. Throughout pregnancy PAPP-A is produced and secreted by the placental syncytiotrophoblast cells; co-incidentally pregnancy-associated breast cancers often have an aggressive clinical course. The components of the PAPP-A/IGF axis was assessed in a panel of breast cancer cell lines. Using neutralising antibodies the impact of PAPP-A/IGF axis on cell motility was evaluated. PAPP-A was expressed in four of the twelve breast cancer cell lines tested. Blocking PAPP-A and IGFBP4 with neutralising antibodies significantly decreased motiliy of MDA-MB-231 cells. Upregulation of PAPP-A expression in breast tumours resulted in a trend towards worse overall survival. Notably, PAPP-A expression also positively correlated with epithelial-to-mesenchymal transition markers. In conclusion, these results indicate that PAPP-A plays an important role in breast cancer progression and it may be a promising therapeutic target in breast cancer.

Highlights

Elevated levels of pregnancy-associated plasma protein-A (PAPP-A) have been implicated in the pathogenesis of various malignancies, including breast cancers
The proteolytic activity of PAPP-A leads to an increase in local free insulin-like growth factor 1 (IGF-1) and activitation of IGF signalling pathway that has a pro-tumorigenic role in c ancers[4]
The diminished motility of MDA-MB-231 was similar to the abrogation of motility previously noted with the anti-PAPP-A and anti-insulin-like growth factor binding protein 4 (IGFBP4) monoclonal antibodies in melanoma cells[8]. This was a proof-of-concept experiment to confirm that the PAPP-A/IGF axis is important in breast cancer and that motile ability can be attenuated by modulation of components of the IGF axis

Summary

Introduction

Elevated levels of pregnancy-associated plasma protein-A (PAPP-A) have been implicated in the pathogenesis of various malignancies, including breast cancers. Throughout pregnancy PAPP-A is produced and secreted by the placental syncytiotrophoblast cells; co-incidentally pregnancy-associated breast cancers often have an aggressive clinical course. The components of the PAPP-A/IGF axis was assessed in a panel of breast cancer cell lines. PAPP-A expression positively correlated with epithelial-to-mesenchymal transition markers. These results indicate that PAPP-A plays an important role in breast cancer progression and it may be a promising therapeutic target in breast cancer. Breast cancer is the second most common cancer type detected in women of child-bearing age, and recurrence in pregnancy-associated breast cancer is correlated with worse o utcome[1]. Nielsen et al detected overexpression of IGF-1R in 87% of 930 patients with primary breast c ancer[13]

Methods

Results

Conclusion