title: Expression of SPRR3 is associated with tumor cell proliferation in less advanced stages of breast cancer.
abstract: Small proline rich repeat protein 3 (SPRR3), a member of the SPRR family of cornified envelope precursor proteins, is a marker for terminal squamous cell differentiation. Previously, this laboratory showed that SPRR3 is strongly upregulated in colorectal tumors, and is involved in the tumorigenesis. The current study was performed to investigate the expression status and effect of SPRR3 in breast cancers (BCs). SPRR3 expression was examined by immunohistochemistry in 241 tumor samples from BC patients. SPRR3 was overexpressed in more than half of all BC samples. SPRR3 overexpression was significantly associated with less advanced stage (0-1 vs. II-III) and the absence of lymph node metastasis (P = 0.004 and 0.013, respectively). HER2/neu overexpression was closely correlated with SPRR3 overexpression in a multivariate analysis (OR, 3.23, P = 0.017). To assess the influence of SPRR3 on cell proliferation and related signaling pathways, SPRR3-transfected clones from the SPRR3-negative T-47D human BC cell line were generated. Among the total of six SPRR3-overexpressing clones, five showed marked proliferation compared with SPRR3-nonexpressing control cells from day 3 of culture (P < 0.001). The SPRR3-overexpressing BC clones showed increased phosphorylation of AKT and MDM2, p21 overexpression, and p53 downregulation. Furthermore, phosphorylation of MEK and MAPK was markedly increased. This study demonstrates that SPRR3 promotes BC cell proliferation by enhancing p53 degradation via the AKT and MAPK pathways and is, therefore, a potential novel therapeutic target for less advanced stages of BC.
authors.affiliation: Department of Surgery, University of Ulsan College of Medicine, Seoul, Republic of Korea. jckim@amc.seoul.kr
authors.forename: Jin Cheon
authors.initials: JC
authors.lastname: Kim
authors.forename: Jong Han
authors.initials: JH
authors.lastname: Yu
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Cho
authors.forename: Choon Sik
authors.initials: CS
authors.lastname: Jung
authors.forename: Sei Hyun
authors.initials: SH
authors.lastname: Ahn
authors.forename: Gyungyub
authors.initials: G
authors.lastname: Gong
authors.forename: Yong Sung
authors.initials: YS
authors.lastname: Kim
authors.forename: Dong-Hyung
authors.initials: DH
authors.lastname: Cho
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055233:Cornified Envelope Proline-Rich Proteins / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009367:Neoplasm Staging; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D055233:Cornified Envelope Proline-Rich Proteins; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases