title: GANP protein encoded on human chromosome 21/mouse chromosome 10 is associated with resistance to mammary tumor development.
abstract: Human chromosome 21 is known to be associated with the high risk of hematological malignancy but with resistance to breast cancer in the study of Down syndrome. In human cancers, we previously observed the significant alterations of the protein expression encoded by the ganp/MCM3AP gene on human chromosome 21q22.3. Here, we investigated GANP protein alterations in human breast cancer samples (416 cases) at various stages by immunohistochemical analysis. This cohort study clearly showed that expression of GANP is significantly decreased in human breast cancer cases with poor prognosis as an independent risk factor (relapse-free survival, hazard ratio = 2.37, 95% confidence interval, 1.27-4.42, P = 0.007 [univariate analysis]; hazard ratio = 2.70, 95% confidence interval, 1.42-5.13, P = 0.002 [multivariate analysis]). To investigate whether the altered GANP expression is associated with mammary tumorigenesis, we created mutant mice that were conditionally deficient in the ganp/MCM3AP gene using wap-cre recombinase transgenic mice. Mammary gland tumors occurred at a very high incidence in female mammary gland-specific GANP-deficient mice after severe impairment of mammary gland development during pregnancy. Moreover, tumor development also occurred in female post parous GANP-heterodeficient mice. GANP has a significant role in the suppression of DNA damage caused by estrogen in human breast cancer cell lines. These results indicated that the GANP protein is associated with breast cancer resistance.
authors.affiliation: Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.|Division of Immunology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kuwahara
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Yamamoto-Ibusuki
authors.affiliation: Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.|Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Zhenhuan
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Suchada
authors.initials: S
authors.lastname: Phimsen
authors.affiliation: Division of Immunology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Gondo
authors.affiliation: Division of Breast and Endocrine Surgery, Hokkaido University Hospital, Sapporo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yamashita
authors.affiliation: Division of Reproductive Engineering, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Takeo
authors.affiliation: Division of Reproductive Engineering, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Nakagata
authors.affiliation: Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamashita
authors.affiliation: Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Fukushima
authors.affiliation: Division of Immunology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Hiroji
authors.initials: H
authors.lastname: Iwata
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Graduate School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.|Department of Cellular and Molecular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Eisaku
authors.initials: E
authors.lastname: Kondo
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Iwase
authors.affiliation: Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.|Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.|WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sakaguchi
mesh_terms: D000123:Acetyltransferases / Q000096:biosynthesis / Q000235:genetics*; D000328:Adult; D000368:Aged; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004967:Estrogens / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D011247:Pregnancy
chemical_list: D004967:Estrogens; D047908:Intracellular Signaling Peptides and Proteins; D000123:Acetyltransferases; C406825:MCM3AP protein, human
keywords: Breast cancer resistance; DNA damage; chromosome 21; down syndrome; ganp/MCM3AP; prognostic factor