GANP protein encoded on human chromosome 21/mouse chromosome 10 is associated with resistance to mammary tumor development.
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.
['Kuwahara|Kazuhiko|K|', 'Yamamoto-Ibusuki|Mutsuko|M|', 'Zhang|Zhenhuan|Z|', 'Phimsen|Suchada|S|', 'Gondo|Naomi|N|', 'Yamashita|Hiroko|H|', 'Takeo|Toru|T|', 'Nakagata|Naomi|N|', 'Yamashita|Daisuke|D|', 'Fukushima|Yoshimi|Y|', 'Yamamoto|Yutaka|Y|', 'Iwata|Hiroji|H|', 'Saya|Hideyuki|H|', 'Kondo|Eisaku|E|', 'Matsuo|Keitaro|K|', 'Takeya|Motohiro|M|', 'Iwase|Hirotaka|H|', 'Sakaguchi|Nobuo|N|']
D000123:Acetyltransferases D000328:Adult D000368:Aged D000818:Animals D001943:Breast Neoplasms D063646:Carcinogenesis D045744:Cell Line, Tumor D002879:Chromosomes, Human, Pair 10 D004249:DNA Damage D004967:Estrogens D005260:Female D015972:Gene Expression Regulation, Neoplastic D006801:Humans D047908:Intracellular Signaling Peptides and Proteins D015674:Mammary Neoplasms, Animal D051379:Mice D008822:Mice, Transgenic D008875:Middle Aged D009364:Neoplasm Recurrence, Local D009367:Neoplasm Staging D011247:Pregnancy
chromosome 21 down syndrome ganp/MCM3AP DNA damage Breast cancer resistance prognostic factor