Increased sensitivity of African American triple negative breast cancer cells to nitric oxide-induced mitochondria-mediated apoptosis

BMC Cancer

Research Article

Luis Martinez¹  Jinna Kim²  Rajan Singh³  Shehla Pervin⁴  Easter Thames⁵  Gautam Chaudhuri⁶ 

[1] California State University, Dominguez Hills, Los Angeles, CA, USA;Charles R. Drew University of Medicine and Science, 90059, Los Angeles, CA, USA;Charles R. Drew University of Medicine and Science, 90059, Los Angeles, CA, USA;Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, 90095, Los Angeles, CA, USA;Jonsson Comprehensive Cancer Center at UCLA, 90095, Los Angeles, CA, USA;Charles R. Drew University of Medicine and Science, 90059, Los Angeles, CA, USA;Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, 90095, Los Angeles, CA, USA;Jonsson Comprehensive Cancer Center at UCLA, 90095, Los Angeles, CA, USA;Division of Endocrinology and Metabolism, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, 90059, Los Angeles, CA, USA;Columbia University New York, 10027, New York, NY, USA;Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, 90095, Los Angeles, CA, USA;Jonsson Comprehensive Cancer Center at UCLA, 90095, Los Angeles, CA, USA;

关键词: Breast cancer;    Health disparity;    African American;    Unique biology;   

DOI  :  10.1186/s12885-016-2547-z

 received in 2016-01-26, accepted in 2016-07-11,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundBreast cancer is a complex heterogeneous disease where many distinct subtypes are found. Younger African American (AA) women often present themselves with aggressive form of breast cancer with unique biology which is very difficult to treat. Better understanding the biology of AA breast tumors could lead to development of effective treatment strategies. Our previous studies indicate that AA but not Caucasian (CA) triple negative (TN) breast cancer cells were sensitive to nitrosative stress-induced cell death. In this study, we elucidate possible mechanisms that contribute to nitric oxide (NO)-induced apoptosis in AA TN breast cancer cells.MethodsBreast cancer cells were treated with various concentrations of long-acting NO donor, DETA-NONOate and cell viability was determined by trypan blue exclusion assay. Apoptosis was determined by TUNEL and caspase 3 activity as well as changes in mitochondrial membrane potential. Caspase 3 and Bax cleavage, levels of Cu/Zn superoxide dismutase (SOD) and Mn SOD was assessed by immunoblot analysis. Inhibition of Bax cleavage by Calpain inhibitor, and levels of reactive oxygen species (ROS) as well as SOD activity was measured in NO-induced apoptosis. In vitro and in vivo effect of NO treatment on mammary cancer stem cells (MCSCs) was assessed.Results and discussionNO induced mitocondria-mediated apoptosis in all AA but not in CA TN breast cancer cells. We found significant TUNEL-positive cells, cleavage of Bax and caspase-3 activation as well as depolarization mitochondrial membrane potential only in AA TN breast cancer cells exposed to NO. Inhibition of Bax cleavage and quenching of ROS partially inhibited NO-induced apoptosis in AA TN cells. Increase in ROS coincided with reduction in SOD activity in AA TN breast cancer cells. Furthermore, NO treatment of AA TN breast cancer cells dramatically reduced aldehyde dehydrogenase1 (ALDH1) expressing MCSCs and xenograft formation but not in breast cancer cells from CA origin.ConclusionsEthnic differences in breast tumors dictate a need for tailoring treatment options more suited to the unique biology of the disease.

【 授权许可】

CC BY   
© The Author(s). 2016