title: Up-regulation of cathepsin S expression by HSP90 and 5-HT7receptor-dependent serotonin signaling correlates with triple negativity of human breast cancer.
abstract: Cathepsin S (CTSS) is expressed in a variety of cancers and stimulates tumor progression. However, the regulatory mechanism and role of CTSS in breast cancer progression are poorly understood. The aim of this study was to examine the relationships between CTSS expression and breast cancer grade and stage, and the signaling molecules involved in CTSS expression.
  
  
  
  Immunohistochemical staining was performed in tissue microarray sections of 1451 human invasive breast cancer samples to determine epithelial (E-CTSS) and stromal CTSS (S-CTSS) expression. Gene and protein expression levels in human breast cancer cell lines were measured by polymerase chain reaction and western blotting. Small interfering RNA transfection and a Matrigel transwell invasion assay were used to confirm the signaling pathways regulating CTSS expression.
  
  
  
  In patient tumor tissue blocks, high grade, late stage, and triple negativity were associated with elevated CTSS protein expression, and expression levels were related to the clinical outcomes of patients with invasive breast cancer. CTSS expression was also higher in triple-negative breast cancer (TNBC) cell lines than in hormone-responsive cells, and CTSS expression patterns matched those of tryptophan hydroxylase 1 (TPH1) and 5-hydroxytryptamine receptor 7 (5-HT7). Treatment of TNBC cells (MDA-MB-231 and HCC-1395) with 5-HT significantly enhanced CTSS protein expression, whereas pharmacological inhibition or knockdown of 5-HT7significantly inhibited its expression. Correspondingly, cancer cell invasion was increased by 5-HT treatment and suppressed by 5-HT7knockdown. The expression of CTSS was regulated by PI3K/Akt and Ras/Raf/MAPK signaling pathways, and these signaling pathways were stabilized by HSP90 and enhanced by the 5-HT7receptor-dependent autocrine effect of 5-HT in TNBC cells.
  
  
  
  Our findings suggest CTSS as a candidate target for development of a strategy to inhibit breast cancer invasion, and indicate that HSP90 and 5-HT7(regulators of CTSS) should be considered as alternative targets for the management of TNBC invasion and metastasis.
authors: College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
authors: Jaya
authors: J
authors: Gautam
authors: Department of Pathology, College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea. ykbae@ynu.ac.kr.
authors: Young Kyung
authors: YK
authors: Bae
authors: College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea. jakim@yu.ac.kr.
authors: Jung-Ae
authors: 0000-0002-0824-8532
authors: JA
authors: Kim
mesh_terms: D000328:Adult; D000368:Aged; D002403:Cathepsins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D040081:Protein Array Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D047368:Tumor Burden; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; D016328:NF-kappa B; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor; D012701:Serotonin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D002403:Cathepsins; C028217:cathepsin S; D018631:ras Proteins
keywords: 5-HT7; Cathepsin S; HSP90; Invasion/metastasis; Triple-negative breast cancer