The Multi-Faced Role of PAPP-A in Post-Partum Breast Cancer: IGF-Signaling is Only the Beginning.
Insulin-like growth factor (IGF) signaling and control of local bioavailability of free IGF by the IGF binding proteins (IGFBP) are important regulators of both mammary development and breast cancer. A recent genome-wide association study (GWAS) identified small nucleotide polymorphisms that reduce the expression of IGFBP-5 as a risk factor of developing breast cancer. This observation suggests that genetic alterations leading to a decreased level of IGFBP-5 may also contribute to breast cancer. In the current review, we focus on Pregnancy-Associated Plasma Protein A (PAPP-A), a protease involved in the degradation of IGFBP-5. PAPP-A is overexpressed in the majority of breast cancers but its role in cancer has only begun to be explored. More specifically, this review aims at highlighting the role of post-partum involution in the oncogenic function of PAPP-A. Notably, we summarize recent studies indicating that PAPP-A plays a role not only in the degradation of IGFBP-5 but also in the deposition of collagen and activation of the collagen receptor discoidin 2 (DDR2) during post-partum involution. Finally, considering the immunosuppressive microenvironment of post-partum involution, we also discuss the unexpected finding made in Ewing Sarcoma that PAPP-A plays a role in immune evasion. While the immunosuppressive role of PAPP-A in breast cancer remains to be determined, collectively these studies highlight the multifaced role of PAPP-A in cancer that extends well beyond its effect on IGF-signaling.
['Jenkins|Edmund Charles|EC|', 'Brown|Samantha O|SO|', 'Germain|Doris|D|']
D000818:Animals D001940:Breast D001943:Breast Neoplasms D000070820:Discoidin Domain Receptor 2 D005260:Female D015972:Gene Expression Regulation, Neoplastic D055106:Genome-Wide Association Study D006801:Humans D018975:Insulin-Like Growth Factor Binding Protein 5 D008321:Mammary Glands, Animal D008325:Mammary Neoplasms, Experimental D051379:Mice D049590:Postpartum Period D011266:Pregnancy-Associated Plasma Protein-A D059748:Proteolysis D015398:Signal Transduction D013002:Somatomedins D059016:Tumor Microenvironment
Breast cancer IGF Involution Collagen Immune evasion DDR Pappalysin-1 Pregnancy