title: Low expression levels of hepsin and TMPRSS3 are associated with poor breast cancer survival.
abstract: BACKGROUND
  Hepsin, (also called TMPRSS1) and TMPRSS3 are type II transmembrane serine proteases (TTSPs) that are involved in cancer progression. TTSPs can remodel extracellular matrix (ECM) and, when dysregulated, promote tumor progression and metastasis by inducing defects in basement membrane and ECM molecules. This study investigated whether the gene and protein expression levels of these TTSPs were associated with breast cancer characteristics or survival.
  
  
  METHODS
  Immunohistochemical staining was used to evaluate hepsin levels in 372 breast cancer samples and TMPRSS3 levels in 373 samples. TMPRSS1 mRNA expression was determined in 125 invasive and 16 benign breast tumor samples, and TMPRSS3 mRNA expression was determined in 167 invasive and 23 benign breast tumor samples. The gene and protein expression levels were analyzed for associations with breast cancer-specific survival and clinicopathological parameters.
  
  
  RESULTS
  Low TMPRSS1 and TMPRSS3 mRNA expression levels were independent prognostic factors for poor breast cancer survival during the 20-year follow-up (TMPRSS1, P = 0.023; HR, 2.065; 95 % CI, 1.106-3.856; TMPRSS3, P = 0.013; HR, 2.106; 95 % CI, 1.167-3.800). Low expression of the two genes at the mRNA and protein levels associated with poorer survival compared to high levels (log rank P-values 0.015-0.042). Low TMPRSS1 mRNA expression was also an independent marker of poor breast cancer prognosis in patients treated with radiotherapy (P = 0.034; HR, 2.344; 95 % CI, 1.065-5.160). Grade III tumors, large tumor size, and metastasis were associated with low mRNA and protein expression levels.
  
  
  CONCLUSIONS
  The results suggest that the TTSPs hepsin and TMPRSS3 may have similar biological functions in the molecular pathology of breast cancer. Low mRNA and protein expression levels of the studied TTSPs were prognostic markers of poor survival in breast cancer.
authors.affiliation: Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. mikkopel@student.uef.fi.|Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. mikkopel@student.uef.fi.|Imaging Center, Clinical Pathology, Kuopio University Hospital, P.O. Box 1777, FI-70211, Kuopio, Finland. mikkopel@student.uef.fi.
authors.forename: Mikko
authors.initials: M
authors.lastname: Pelkonen
authors.affiliation: Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. kaisa.luostari@uef.fi.|Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. kaisa.luostari@uef.fi.|Imaging Center, Clinical Pathology, Kuopio University Hospital, P.O. Box 1777, FI-70211, Kuopio, Finland. kaisa.luostari@uef.fi.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Luostari
authors.affiliation: Institute of Clinical Medicine, Oncology, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. maria.tengstrom@kuh.fi.|Cancer Center, Kuopio University Hospital, P.O. Box 1777, FI-70211, Kuopio, Finland. maria.tengstrom@kuh.fi.
authors.forename: Maria
authors.initials: M
authors.lastname: Tengström
authors.affiliation: Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. herma@student.uef.fi.|Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. herma@student.uef.fi.|Imaging Center, Clinical Pathology, Kuopio University Hospital, P.O. Box 1777, FI-70211, Kuopio, Finland. herma@student.uef.fi.
authors.forename: Hermanni
authors.initials: H
authors.lastname: Ahonen
authors.affiliation: Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. bozena.berdel@uef.fi.|Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. bozena.berdel@uef.fi.|Imaging Center, Clinical Pathology, Kuopio University Hospital, P.O. Box 1777, FI-70211, Kuopio, Finland. bozena.berdel@uef.fi.
authors.forename: Bozena
authors.initials: B
authors.lastname: Berdel
authors.affiliation: Institute of Clinical Medicine, Oncology, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. vesa.kataja@ksshp.fi.|Cancer Center, Kuopio University Hospital, P.O. Box 1777, FI-70211, Kuopio, Finland. vesa.kataja@ksshp.fi.
authors.forename: Vesa
authors.initials: V
authors.lastname: Kataja
authors.affiliation: Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. ylermi.soini@uef.fi.|Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. ylermi.soini@uef.fi.|Imaging Center, Clinical Pathology, Kuopio University Hospital, P.O. Box 1777, FI-70211, Kuopio, Finland. ylermi.soini@uef.fi.
authors.forename: Ylermi
authors.initials: Y
authors.lastname: Soini
authors.affiliation: Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. veli-matti.kosma@uef.fi.|Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. veli-matti.kosma@uef.fi.|Imaging Center, Clinical Pathology, Kuopio University Hospital, P.O. Box 1777, FI-70211, Kuopio, Finland. veli-matti.kosma@uef.fi.
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kosma
authors.affiliation: Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. arto.mannermaa@uef.fi.|Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. arto.mannermaa@uef.fi.|Imaging Center, Clinical Pathology, Kuopio University Hospital, P.O. Box 1777, FI-70211, Kuopio, Finland. arto.mannermaa@uef.fi.
authors.forename: Arto
authors.initials: A
authors.lastname: Mannermaa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D047368:Tumor Burden; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012697:Serine Endopeptidases; C409042:TMPRSS3 protein, human; C055645:hepsin