TY - JOUR
T1 - Breast cancers with high DSS1 expression that potentially maintains BRCA2 stability have poor prognosis in the relapse-free survival
AU - Rezano, Andri
AU - Kuwahara, Kazuhiko
AU - Yamamoto-Ibusuki, Mutsuko
AU - Kitabatake, Masahiro
AU - Moolthiya, Penpak
AU - Phimsen, Suchada
AU - Suda, Taiji
AU - Tone, Shigenobu
AU - Yamamoto, Yutaka
AU - Iwase, Hirotaka
AU - Sakaguchi, Nobuo
N1 - Funding Information:
We would like to thank Mika Ito for technical assistance. This work was supported by Grant-in Aid from the Ministry of Education, Culture, Sports, Science, and Technology in Japan (KK and NS) and by a contract research fund from the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases (NS). AR is supported by an Indonesian Directorate General of Higher Education (DIKTI) Scholarship.
PY - 2013/12/1
Y1 - 2013/12/1
N2 - Background: Genetic BRCA2 insufficiency is associated with breast cancer development; however, in sporadic breast cancer cases, high BRCA2 expression is paradoxically correlated with poor prognosis. Because DSS1, a mammalian component of the transcription/RNA export complex, is known to stabilize BRCA2, we investigated how the expression of DSS1 is associated with clinical parameters in breast cancers. Methods: DSS1 mRNA and p53 protein were examined by RT-PCR and immunohistochemical staining of breast cancer specimens to classify DSS1high and DSS1low or p53high and p53low groups. Patient survival was compared using Kaplan-Meier method. DSS1high or DSS1low breast cancer cells were prepared by retroviral cDNA transfection or DSS1 siRNA on proliferation, cell cycle progression, and survival by flow cytometric analyses with or without anti-cancer drugs. Results: In comparison to patients with low levels of DSS1, high-DSS1 patients showed a poorer prognosis, with respect to relapse-free survival period. The effect of DSS1 was examined in breast cancer cells in vitro. DSS1 high-expression reduces the susceptibility of MCF7 cells to DNA-damaging drugs, as observed in cell cycle and apoptosis analyses. DSS1 knockdown, however, increased the susceptibility to the DNA-damaging drugs camptothecin and etoposide and caused early apoptosis in p53 wild type MCF7 and p53-insufficient MDA-MB-231 cells. DSS1 knockdown suppresses the proliferation of drug-resistant MDA-MB-231 breast cancer cells, particularly effectively in combination with DNA-damaging agents. Conclusion: Breast cancers with high DSS1 expression have worse prognosis and shorter relapse-free survival times. DSS1 is necessary to rescue cells from DNA damage, but high DSS1 expression increases drug resistance. We suggest that DSS1 expression could be a useful marker for drug resistance in breast cancers, and DSS1 knockdown can induce tumor apoptosis when used in combination with DNA-damaging drugs.
AB - Background: Genetic BRCA2 insufficiency is associated with breast cancer development; however, in sporadic breast cancer cases, high BRCA2 expression is paradoxically correlated with poor prognosis. Because DSS1, a mammalian component of the transcription/RNA export complex, is known to stabilize BRCA2, we investigated how the expression of DSS1 is associated with clinical parameters in breast cancers. Methods: DSS1 mRNA and p53 protein were examined by RT-PCR and immunohistochemical staining of breast cancer specimens to classify DSS1high and DSS1low or p53high and p53low groups. Patient survival was compared using Kaplan-Meier method. DSS1high or DSS1low breast cancer cells were prepared by retroviral cDNA transfection or DSS1 siRNA on proliferation, cell cycle progression, and survival by flow cytometric analyses with or without anti-cancer drugs. Results: In comparison to patients with low levels of DSS1, high-DSS1 patients showed a poorer prognosis, with respect to relapse-free survival period. The effect of DSS1 was examined in breast cancer cells in vitro. DSS1 high-expression reduces the susceptibility of MCF7 cells to DNA-damaging drugs, as observed in cell cycle and apoptosis analyses. DSS1 knockdown, however, increased the susceptibility to the DNA-damaging drugs camptothecin and etoposide and caused early apoptosis in p53 wild type MCF7 and p53-insufficient MDA-MB-231 cells. DSS1 knockdown suppresses the proliferation of drug-resistant MDA-MB-231 breast cancer cells, particularly effectively in combination with DNA-damaging agents. Conclusion: Breast cancers with high DSS1 expression have worse prognosis and shorter relapse-free survival times. DSS1 is necessary to rescue cells from DNA damage, but high DSS1 expression increases drug resistance. We suggest that DSS1 expression could be a useful marker for drug resistance in breast cancers, and DSS1 knockdown can induce tumor apoptosis when used in combination with DNA-damaging drugs.
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U2 - 10.1186/1471-2407-13-562
DO - 10.1186/1471-2407-13-562
M3 - Article
C2 - 24289229
AN - SCOPUS:84888315283
VL - 13
JO - BMC Cancer
JF - BMC Cancer
SN - 1471-2407
M1 - 562
ER -