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The identification of novel biomarkers for early prostate cancer diagnosis is highly important because early detectionand treatment are critical for the medical management of patients.Disruption in the continuity of both the basal celllayer and basement membrane is essential for the progression of high-grade prostatic intraepithelial neoplasia (HGPIN)to invasive adenocarcinoma in human prostate.The molecules involved in the conversion to an invasive phenotype arethe subject of intense scrutiny.We have previously reported that matrix metalloproteinase-26 (MMP-26) promotes theinvasion of human prostate cancer cells via the cleavage of basement membrane proteins and by activating the zymogenform of MMP-9.Furthermore,we have found that tissue inhibitor of metalloproteinases-4 (TIMP-4) is the most potentendogenous inhibitor of MMP-26.Here we demonstrate higher (p<0.0001) MMP-26 and TIMP-4 expression in HGPINand cancer,compared to non-neoplastic acini.Their expression levels are highest in HGP1N,but decline in invasive cancer(p<0.001 for each) in the same tissues.Immunohistochemical staining of serial prostate cancer tissue sections suggestscolocalization of MMP-26 and TIMP-4.The present study indicates that MMP-26 and TIMP-4 may play an integral roleduring the conversion of HGPIN to invasive cancer and may also serve as markers for early prostate cancer diagnosis.