Abstract
BackgroundFibroblast Activation Protein alpha (FAP-α) or seprase is an integral membrane serine peptidase. Previous work has not satisfactorily explained both the suppression and promotion effects that have been observed in cancer. The purpose of this work was to investigate the role of FAP-α in human breast cancer. Expression of FAP-α was characterized in primary tumour samples and in cell lines, along with the effects of FAP-α expression on in vitro growth, invasion, attachment and migration. Furthermore the potential interaction of FAP-α with other signalling pathways was investigated.ResultsFAP-α was significantly increased in patients with poor outcome and survival. In vitro results showed that breast cancer cells over expressing FAP-α had increased growth ability and impaired migratory ability. The growth of MDA-MB-231 cells and the adhesion and invasion ability of both MCF-7 cells and MDA-MB-231 cells were not dramatically influenced by FAP-α expression. Over-expression of FAP-α resulted in a reduction of phosphorylated focal adhesion kinase (FAK) level in both cells cultured in normal media and serum-free media. An inhibitor to FAK restored the reduced motility ability of both MCF-7exp cells and MDA-MB-231exp cells and prevented the change in phosphorylated FAK levels. However, inhibitors to PI3K, ERK, PLCϒ, NWASP, ARP2/3, and ROCK had no influence this.ConclusionsFAP-α in significantly associated with poor outcome in patients with breast cancer. In vitro, FAP-α promotes proliferation and inhibits migration of breast cancer cells, potentially by regulating the FAK pathway. These results suggest FAP-α could be a target for future therapies.
Highlights
Fibroblast Activation Protein alpha (FAP-α) or seprase is an integral membrane serine peptidase
Expression of Fibroblast Activation Protein-α (FAP-α) in breast tumour is correlated with patient prognosis and survival Analysis carried out using Q-Polymerase chain reaction (PCR) revealed that patients with poor outcome had the highest levels of FAP-α (Figure 1A)
(See figure on previous page.) Figure 4 Effect on FAP-α overexpression and cellular behaviour. (A) Increased invasion was observed in both MCF7 and MDA-MB-231 cells Overexpressing FAP-α (n = 8). (B) Adhesion to basement membrane showed that MCF7exp cells exhibited lower adhesion but that MDA-MB-231exp cells were more adhesive (n = 8). (C, top) Electric Cell-substrate Impedance Sensing (ECIS) experiments showed that MCF7exp cell showed reduced attachment after 2 hour, whereas MDA-MB-231exp attachment was increased (C, bottom). (D) In the migration phase, motility of both MCF7exp cells and MDA-MB-231exp cells was dramatically reduced compared to the wild type and control cells (n = 16)
Summary
Fibroblast Activation Protein alpha (FAP-α) or seprase is an integral membrane serine peptidase. The purpose of this work was to investigate the role of FAP-α in human breast cancer. Fibroblast Activation Protein alpha (FAP-α) or Seprase is a member of the serine integral membrane peptidases (SIMPs) family which includes prolylendopeptidase, dipeptidyl peptidase IV (DPPIV or CD26), and dipeptidyl peptidase IIX. These peptidases are inducible, specific for proline-containing peptides, and are active on the cell surface [1,2]. Other studies have shown that FAP-α expression is not confined to stromal fibroblasts but that it is expressed in some epithelial malignant cells. It has been demonstrated that FAP-α is highly expressed on the surface of glioma cells, bone and soft tissue tumour cells [10,11]
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