title: Elevated NRD1 metalloprotease expression plays a role in breast cancer growth and proliferation.
abstract: Understanding the molecular etiology of cancer and increasing the number of drugs and their targets are critical to cancer management. In our attempt to unravel novel breast-cancer associated proteins, we previously conducted protein expression profiling of the MCF10AT model, which comprises a series of isogenic cell lines that mimic different stages of breast cancer progression. NRD1 expression was found to increase during breast cancer progression. Here, we attempted to confirm the relevance of NRD1 in clinical breast cancer and understand the functional role and mechanism of NRD1 in breast cancer cells. Immunohistochemistry data show that NRD1 expression was elevated in ductal carcinoma in situ and invasive ductal carcinomas compared with normal tissues in 30% of the 26 matched cases studied. Examination of NRD1 expression in tissue microarray comprising >100 carcinomas and subsequent correlation with clinical data revealed that NRD1 expression was significantly associated with tumor size, grade, and nodal status (P < 0.05). Silencing of NRD1 reduced MCF10CA1h and MDA-MD-231 breast-cancer-cell proliferation and growth. Probing the oncogenic EGF signaling pathways revealed that NRD1 knock down did not affect overall downstream tyrosine phosphorylation cascades including AKT and MAPK activation. Instead, silencing of NRD1 resulted in a reduction of overall cyclin D1 expression, a reduction of EGF-induced increase in cyclin D1 expression and an increase in apoptotic cell population compared with control cells.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 28 Medical Drive, Centre for Life Sciences, Singapore.
authors.forename: Lee-Yee
authors.initials: LY
authors.lastname: Choong
authors.forename: Shen-Kiat
authors.initials: SK
authors.lastname: Lim
authors.forename: Yunhao
authors.initials: Y
authors.lastname: Chen
authors.forename: Marie-Chiew-Shia
authors.initials: MC
authors.lastname: Loh
authors.forename: Weiyi
authors.initials: W
authors.lastname: Toy
authors.forename: Chow-Yin
authors.initials: CY
authors.lastname: Wong
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.forename: Nilesh
authors.initials: N
authors.lastname: Shah
authors.forename: Yoon-Pin
authors.initials: YP
authors.lastname: Lim
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D034741:RNA, Small Interfering; D019938:Cyclin D1; D014443:Tyrosine; D004815:Epidermal Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D045726:Metalloproteases