title: Targeting MCM2 function as a novel strategy for the treatment of highly malignant breast tumors.
abstract: Highly malignant tumors express high levels of the minichromosome maintenance 2 (MCM2) protein, which is associated with advanced tumor grade, advanced stage, and poor prognosis. In a previous study, we showed that Friend leukemia virus (FLV) envelope protein gp70 bound MCM2, impaired its nuclear translocation, and enhanced DNA-damage-induced apoptosis in FLV-infected hematopoietic cells when the cells expressed high levels of MCM2. Here, we show that MCM2 is highly expressed in clinical samples of invasive carcinoma of the breast, especially triple-negative breast cancer (TNBC), and in cancer stem cell (CSC) marker-positive breast cancer cells. To generate a cancer therapy model using gp70, we introduced the gp70 protein into the cytoplasm of murine breast cancer cells that express high levels of MCM2 by conjugating the protein transduction domain (PTD) of Hph-1 to gp70 (Hph-1-gp70). Hph-1-gp70 was successfully transduced into the cytoplasm of breast cancer cells. The transduced protein enhanced the DNA damage-induced apoptosis of cancer cells in vitro and in vivo. Therefore, an MCM2-targeted strategy using Hph-1-gp70 treatment to induce DNA damage might be a successful therapy for highly malignant breast cancers such as TNBC and for the eradication of CSC-like cells from breast cancer tissue.
authors.affiliation: Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Abe
authors.affiliation: Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Morito
authors.initials: M
authors.lastname: Kurata
authors.affiliation: Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Abe-Suzuki
authors.affiliation: Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Horii
authors.affiliation: Department of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Akiyama
authors.affiliation: Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kitagawa
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D064111:Minichromosome Maintenance Complex Component 2 / Q000096:biosynthesis*; D063150:Polycomb Repressive Complex 1 / Q000494:pharmacology; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015682:Retroviridae Proteins, Oncogenic / Q000494:pharmacology; D014161:Transduction, Genetic; D014162:Transfection; D014759:Viral Envelope Proteins / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C491239:PHC1 protein, human; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D015682:Retroviridae Proteins, Oncogenic; D014759:Viral Envelope Proteins; C073723:glycoprotein gp70, Feline leukemia virus; D063150:Polycomb Repressive Complex 1; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2
keywords: DNA-damage; MCM2; apoptosis; breast cancer; cancer stem cell