Amplification of MUC1 in prostate cancer metastasis and CRPC development.
Evidence supports the upregulation of MUC1 in prostate cancer (PC). However, this has not been thoroughly investigated. We report here an association of MUC1 upregulation with PC metastasis and the development of castration resistant PC (CRPC). MUC1 expression was specifically increased in DU145 cell-derived PC stem-like cells (PCSLCs) in comparison to their non-PCSLCs counterparts. While immunohistochemistry staining of 34 primary PCs revealed variability in MUC1 expression, Nanostring technology demonstrated elevated MUC1 mRNA levels in 4 of 7 PCs compared to their normal matched tissues. By analyzing MUC1 mRNA levels and gene copy number (GCN) using the OncomineTM database, elevations in MUC1 mRNA in 82 metastases versus 280 primary PCs and in MUC1 GCN in 37 metastases over 181 primary tumors were demonstrated. Analysis of genomic datasets within cBioPortal revealed increases in MUC1 GCN in 2% (6/333) of primary PCs, 6% (9/150) of metastatic PCs, and 33% (27/82) of CRPCs; in comparison, the respective increase in androgen receptor (AR) GCN was 1%, 63%, and 56%, revealing a specific increase in MUC1 GCN for CRPC. Furthermore, a 25-gene MUC1 network was amplified in 52% of CRPCs compared to 69% of CRPCs displaying increases in an AR co-regulator group. While genomic alterations in the MUC1 network largely overlap with those in the AR group, 18 CRPCs (66.7% being neuroendocrine PC) showed genomic alterations only in the MUC1 network. Moreover, genomic alterations in the MUC1 network correlated with PC relapse. Collectively, our observations suggest a combination therapy involving MUC1-based immunotherapy and androgen deprivation.
Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.|Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada.|The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, Ontario, Canada.
Nicholas
N
Wong
Division of Medical Oncology, Department of Oncology, McMaster University, Hamilton, Ontario, Canada.
Pierre
P
Major
Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada.|Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
Anil
A
Kapoor
Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.|Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada.|The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, Ontario, Canada.|The Genetics Laboratory, Longgang District Maternity and Child Healthcare Hospital, Longgang District, Shenzhen, Guangdong, P.R. China.
Fengxiang
F
Wei
Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.|Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada.|The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, Ontario, Canada.
Judy
J
Yan
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Tariq
T
Aziz
Department of Respiratory Medicine, Shenzhen 2nd People's Hospital, Shenzhen, Guangdong, China.|Department of Respiratory Disease, The First Affiliated Hospital of Shenzhen University Medical School, Shenzhen, Guangdong, China.
Mingxing
M
Zheng
Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.|Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada.|The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, Ontario, Canada.
Dulitha
D
Jayasekera
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Jean-Claude
JC
Cutz
Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.|Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada.|The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, Ontario, Canada.
Mathilda Jing
MJ
Chow
Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.|Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada.|The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, Ontario, Canada.
Damu
D
Tang
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000556:secondary / Q000628:therapy; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D019295:Computational Biology; D030541:Databases, Genetic; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D005784:Gene Amplification; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D018396:Mucin-1 / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000378:metabolism / Q000556:secondary / Q000628:therapy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D043823:Taxoids / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
C410798:AR protein, human; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; C060192:MUC1 protein, human; D018396:Mucin-1; D012333:RNA, Messenger; D011944:Receptors, Androgen; D043823:Taxoids; D000077143:Docetaxel
MUC1; castration resistant prostate cancer; metastasis; prostate cancer; prostate cancer stem cells