Breast cancer is the leading cause of mortality in women and is the second most common malignancy encountered in women of childbearing age. An aggressive clinical course has been reported to occur during pregnancy. Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase that cleaves insulin-like growth factor 1 (IGF-1) from a circulating complex formed with insulin-like growth factor binding protein 4 (IGFBP4). Increased bioavailability of IGF1 subsequently impacts on tumour biology. PAPP-A is produced in increasing levels until term by the syncytiotrophoblast cells in the human placenta. High levels of PAPP-A have been associated with progression in other tumour types.
Eleven breast cancer cell lines were examined to characterise the components of the PAPP-A/IGF axis in breast cancer. PAPP-A mRNA expression was analysed by quantitative RT-PCR. The effect of PAPP-A expression on cell migration in the MDA-MB-453 cell line was subsequently evaluated by using neutralising antibodies. An analysis of The Cancer Genome Atlas (TCGA) publicly available transcriptome profiling dataset was also performed, through specific query of expression clustering.
PAPP-A expression was noted in three of the cell lines. In the MDA-MB-453 cell line, which expressed high levels of PAPP-A, neutralising antibodies to PAPP-A and IGFBP4 significantly reduced migratory capabilities. Analysis of the TCGA dataset revealed that alteration (mainly upregulation) in PAPP-A expression resulted in worse overall survival (n = 1104, p = 0.13). Median survival with alteration in PAPP-A expression was 74 months compared with 113 months in patients without alteration in PAPP-A.
Our data suggest that PAPP-A plays a role in the progression of breast cancer, which may be particularly relevant in pregnancy. The insights gained from this research open up the possibility of indirect and specific therapeutic targeting of IGF to halt the progression of breast cancer.
Clinical trial identification
Legal entity responsible for the study
Olivia Newton-John Cancer Research Institute
J. Cebon: Jonathan S. Cebon Honoraria - Amgen; Bristol-Myers Squibb; GlaxoSmithKline; Merck; Merck Sharp & Dohme; Merck Sharp & Dohme; Merck Sharp & Dohme; Novartis Consulting or Advisory Role - Amgen (Inst); Bionomics; Bionomics (Inst); Bristol-Myers Squibb (Inst); Bristol-Myers Squibb (Inst); Bristol-Myers Squibb (Inst); Bristol-Myers Squibb (Inst); Bristol-Myers Squibb (Inst); Merck Sharp & Dohme (Inst); Merck Sharp & Dohme (Inst); Merck Sharp & Dohme (Inst); Novartis; Novartis (Inst) Research Funding - CSL (Inst); GlaxoSmithKline (Inst) Patents, Royalties, Other Intellectual Property - GlaxoSmithKline Expert Testimony - Bristol-Myers Squibb
All other authors have declared no conflicts of interest.