title: Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling.
abstract: We previously described a gene signature for breast cancer stem cells (BCSCs) derived from patient biopsies. Selective shRNA knockdown identified ribosomal protein L39 (RPL39) and myeloid leukemia factor 2 (MLF2) as the top candidates that affect BCSC self-renewal. Knockdown of RPL39 and MLF2 by specific siRNA nanoparticles in patient-derived and human cancer xenografts reduced tumor volume and lung metastases with a concomitant decrease in BCSCs. RNA deep sequencing identified damaging mutations in both genes. These mutations were confirmed in patient lung metastases (n = 53) and were statistically associated with shorter median time to pulmonary metastasis. Both genes affect the nitric oxide synthase pathway and are altered by hypoxia. These findings support that extensive tumor heterogeneity exists within primary cancers; distinct subpopulations associated with stem-like properties have increased metastatic potential.
authors.affiliation: Houston Methodist Cancer Center, Houston, TX 77030;
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Dave
authors.affiliation: Houston Methodist Cancer Center, Houston, TX 77030;
authors.forename: Sergio
authors.initials: S
authors.lastname: Granados-Principal
authors.affiliation: Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030;
authors.forename: Rui
authors.initials: R
authors.lastname: Zhu
authors.affiliation: Five3 Genomics, Santa Cruz, CA 95060;
authors.forename: Stephen
authors.initials: S
authors.lastname: Benz
authors.affiliation: Chan Soon-Shiong Institute for Advanced Health, Culver City, CA 90232;
authors.forename: Shahrooz
authors.initials: S
authors.lastname: Rabizadeh
authors.affiliation: Chan Soon-Shiong Institute for Advanced Health, Culver City, CA 90232;
authors.forename: Patrick
authors.initials: P
authors.lastname: Soon-Shiong
authors.affiliation: Department of Breast Surgery, Shanghai Cancer Center and Cancer Institute of Fudan University, Shanghai 200032, China;
authors.forename: Ke-Da
authors.initials: KD
authors.lastname: Yu
authors.affiliation: Department of Breast Surgery, Shanghai Cancer Center and Cancer Institute of Fudan University, Shanghai 200032, China;
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Univestity of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Xiaoxian
authors.initials: X
authors.lastname: Li
authors.affiliation: Univestity of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Michael
authors.initials: M
authors.lastname: Gilcrease
authors.affiliation: Greehey Children's Cancer Research Institute.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Lai
authors.affiliation: Greehey Children's Cancer Research Institute,Department of Epidemiology and Biostatistics.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Molecular Medicine, andCancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229;
authors.forename: Tim H-M
authors.initials: TH
authors.lastname: Huang
authors.affiliation: Department of NanoMedicine, Houston Methodist Research Institute, Houston, TX 77030;
authors.forename: Haifa
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of NanoMedicine, Houston Methodist Research Institute, Houston, TX 77030;
authors.forename: Xuewu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of NanoMedicine, Houston Methodist Research Institute, Houston, TX 77030;
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.affiliation: Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030;
authors.forename: Ming
authors.initials: M
authors.lastname: Zhan
authors.affiliation: Houston Methodist Cancer Center, Houston, TX 77030;Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030;
authors.forename: Stephen T C
authors.initials: ST
authors.lastname: Wong
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute andDepartment of Pathology and Genomic Medicine, Houston Methodist Hospital System, Houston, TX 77030; and.
authors.forename: Muthiah
authors.initials: M
authors.lastname: Kumaraswami
authors.affiliation: Weill Cornell Medical College, New York, NY 10065.
authors.forename: Vivek
authors.initials: V
authors.lastname: Mittal
authors.affiliation: Weill Cornell Medical College, New York, NY 10065.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Weill Cornell Medical College, New York, NY 10065.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Gross
authors.affiliation: Houston Methodist Cancer Center, Houston, TX 77030; jcchang@houstonmethodist.org.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000517:prevention & control; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000860:Hypoxia; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology*; D009569:Nitric Oxide / Q000737:chemistry; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012269:Ribosomal Proteins / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D013997:Time Factors
chemical_list: C100853:MLF2 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C471571:RPL39L protein, human; D012269:Ribosomal Proteins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase