Fibroblast activation
protein-α (FAP) is a cell surface,
serine protease of the post-prolyl
peptidase family that is expressed in human
breast cancer but not in normal tissues. Previously, we showed that FAP expression increased
tumor growth rates in a mouse model of human
breast cancer. Here the role of the proteolytic activities of FAP in promoting
tumor growth, matrix degradation and invasion was investigated. Mammary fat pads of female SCID mice were inoculated with
breast cancer cells that express FAP and the mice treated with
normal saline or Val-boroPro (
talabostat); Glu-boroPro (PT-630); or 1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-
pyrrolidine (LAF-237) that inhibit prolyl
peptidases. Other mice were injected with
breast cancer cells expressing a catalytically inactive mutant of FAP and did not receive inhibitor treatment. PT-630 and
LAF-237 did not slow growth of
tumors produced by any of the three cell lines expressing FAP.
Talabostat slightly decreased the growth rates of the FAP-expressing
tumors but because PT-630 and
LAF-237 did not, the growth retardation was likely not related to the inhibition of FAP or the related post-prolyl
peptidase dipeptidyl peptidase IV.
Breast cancer cells expressing a catalytically inactive mutant of FAP (FAP(S624A)) also produced
tumors that grew rapidly. In vitro studies revealed that cells expressing wild type FAP or FAP(S624A) degrade extracellular matrix (ECM) more extensively, accumulate higher levels of
matrix metalloproteinase-9 (MMP-9) in
conditioned medium, are more invasive in
type I collagen gels, and have altered signaling compared to control transfectants that do not express FAP and form slow growing
tumors. We conclude that the proteolytic activity of FAP participates in matrix degradation, but other functions of the
protein stimulate increased
tumor growth.