Γ-secretase components as predictors of breast cancer outcome.
γ-secretase is a large ubiquitously expressed protease complex composed of four core subunits: presenilin, Aph1, PEN-2, and nicastrin. The function of γ-secretase in the cells is to proteolytically cleave various proteins within their transmembrane domains. Presenilin and Aph1 occur as alternative variants belonging to mutually exclusive γ-secretase complexes and providing the complexes with heterogeneous biochemical and physiological properties. γ-secretase is proposed to have a role in the development and progression of cancer and γ-secretase inhibitors are intensively studied for their probable anti-tumor effects in various types of cancer models. Here, we for the first time determined mRNA expression levels of presenilin-1, presenilin-2, Aph1a, Aph1b, PEN-2, and nicastrin in a set of breast cancer tissue samples (N = 55) by quantitative real-time PCR in order to clarify the clinical significance of the expression of different γ-secretase complex components in breast cancer. We found a high positive correlation between the subunit expression levels implying a common regulation of transcription. Our univariate Kaplan-Meier survival analyses established low expression level of γ-secretase complex as a risk factor for breast cancer specific mortality. The tumors expressing low levels of γ-secretase complex were characterized by high histopathological tumor grade, low or no expression of estrogen and progesterone receptors and consequently high probability to fall into the class of triple negative breast cancer tumors. These results may provide novel tools to further categorize breast cancer tumors, especially the highly aggressive and poorly treatable breast cancer type of triple negative cases, and suggest a significant role for γ-secretase in breast cancer.
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland ; Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland ; Imaging Center, Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
Hanna M
HM
Peltonen
Annakaisa
A
Haapasalo
Mikko
M
Hiltunen
Vesa
V
Kataja
Veli-Matti
VM
Kosma
Arto
A
Mannermaa
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D010450:Endopeptidases; D047628:Estrogen Receptor alpha / Q000235:genetics; D047629:Estrogen Receptor beta / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D060787:Neoplasm Grading; D010447:Peptide Hydrolases / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D053766:Presenilin-2 / Q000235:genetics; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D014158:Transcription, Genetic; D064726:Triple Negative Breast Neoplasms / Q000235:genetics
D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010447:Peptide Hydrolases; D053764:Presenilin-1; D053766:Presenilin-2; D018719:Erb-b2 Receptor Tyrosine Kinases; C469349:PSENEN protein, human; C413604:nicastrin protein; C475154:APH1A protein, human; C475155:APH1B protein, human