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

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. Breast cancer is a common malignancy, and prognosis of metastatic disease is significantly worse; thus, there is a pressing need for additional treatment strategies to impede progression of the disease. 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 outcome 1. Triple-negative breast cancers (negative for expression of the oestrogen receptor [ER], the progesterone receptor [PR], and Her2) account for 10-20% of breast cancers, and have been reported to be more aggressive and associated with poorer survival than Her2 or hormone receptorpositive breast cancers 2. Notably, although hormone receptor-positive tumours far outweigh the triple-negative subtype in general, and hormone levels change substantially during pregnancy, the triple-negative subtype of breast cancer is encountered more often than hormone receptor-positive tumours in pregnancy, suggesting an alternative mechanism of cancer promotion in pregnancy 3. The metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A) cleaves the insulin-like growth factor binding protein 4 (IGFBP4) and insulin-like growth factor 1 (IGF-1) complex 4. The proteolytic activity of PAPP-A leads to an increase in local free IGF-1 and activitation of IGF signalling pathway that has a pro-tumorigenic role in cancers 4. PAPP-A was first identified in the plasma of pregnant women in 1974 and is secreted by placental syncytiotrophoblast cells, subsequently released into the maternal circulation. Secreted PAPP-A concentration rise exponentially in the first trimester. Its levels continue to rise throughout pregnancy

Characterisation of the Stromal Microenvironment in Lobular Breast Cancer

“…PAPPA was the most enriched gene in the TS compared to TE in ILC. Of the few immunohistochemical studies reporting on PAPP-A in breast tumors, only expression in the tumor epithelium has been recorded [ 29 , 30 , 52 ]. However, we found that both PAPPA and IGF1 were predominantly expressed in the stroma of ILC, while IGF1R was expressed within the tumor epithelium.…”

Crosstalk between Immune Checkpoint Modulators, Metabolic Reprogramming and Cellular Plasticity in Triple-Negative Breast Cancer

“…It accounts for 12% of all new cancer cases and 25% of all types of cancer in women [ 1 , 2 ]. At the molecular level, based on hormone receptor status, breast cancers are categorized as Luminal A (estrogen receptor (ER)+, progesterone receptor (PR)+, and human epidermal receptor 2 (HER2)-); Luminal B (ER+ and/or PR+, HER2+/−); HER2 enriched (ER-, PR- and HER2+); and Basal-like including triple negative (ER-, PR- and HER2-) breast cancers [ 3 ]. Among these subtypes, triple-negative breast cancer (TNBC) accounts for about 15–20% of all breast cancer types, and it is the most aggressive subtype associated with a very dismal prognosis [ 4 , 5 ].…”

“…The mortality rate of TNBC patients within 3 months after recurrence is as high as 75% [ 7 , 8 ]. Frequently, pregnancy associated breast cancers display a higher incidence of the TNBC phenotype and have a poorer prognosis [ 3 , 5 ].…”