title: Multidrug resistance protein 4 (MRP4) expression in prostate cancer is associated with androgen signaling and decreases with tumor progression.
abstract: Multidrug resistance protein 4 (MRP4) is a transmembrane transport protein found in many cell types and is involved in substrate-specific transport of endogenous and exogenous substrates. Recently, it has shown to be expressed in prostate cancer cell lines and to be among the most commonly upregulated transcripts in prostate cancer, although a comprehensive expression analysis is lacking so far. We aimed to investigate its expression by immunohistochemistry in a larger cohort of neoplastic and nonneoplastic prostate tissues (n = 441) and to correlate its expression with clinicopathological parameters including PSA-free survival times and molecular correlates of androgen signaling (androgen receptor (AR), prostate-specific antigen (PSA), and forkhead box A (FoxA)). MRP4 is widely expressed in benign and neoplastic prostate epithelia, but its expression gradually decreases during tumor progression towards castrate-resistant disease. Concordantly, it correlated with conventional prognosticators of disease progression and-within the group of androgen-dependent tumors-with AR and FoxA expression. Moreover, lower levels of MRP4 expression were associated with shorter PSA relapse-free survival times in the androgen-dependent group. In benign tissues, we found zone-dependent differences of MRP4 expression, with the highest levels in the peripheral and central zones. Although MRP4 is known to be regulated in prostate cancer, this study is the first to demonstrate a gradual downregulation of MRP4 protein during malignant tumor progression and a prognostic value of this loss of expression.
authors.affiliation: Division of Clinical Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Matteo
authors.initials: M
authors.lastname: Montani
authors.forename: Thomas
authors.initials: T
authors.lastname: Hermanns
authors.forename: Thomas
authors.initials: T
authors.lastname: Herrmanns
authors.forename: Michael
authors.initials: M
authors.lastname: Müntener
authors.forename: Peter
authors.initials: P
authors.lastname: Wild
authors.forename: Tullio
authors.initials: T
authors.lastname: Sulser
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000032:analysis / Q000502:physiology*; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000401:mortality / Q000473:pathology*; D011944:Receptors, Androgen / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017430:Prostate-Specific Antigen; D011944:Receptors, Androgen; C073492:ABCC4 protein, human; C410798:AR protein, human