Abstract
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.
Highlights
Breast cancer is a complex heterogeneous disease where many distinct subtypes are found
Nitric Oxide preferentially induced cell death in AA triple negative (TN) breast cancer cells Effect of nitric oxide (NO) on viability and proliferation of breast cancer cell was examined by treatment with various concentrations of DETA NONOate, a long acting NO-donor
In all the four CA cell lines, no apparent cell death was observed at low concentrations of NO, while at high concentrations only 20-28 % cell death was observed at 48h in both MDA-MB-231 (27.07 ± 4.56 %) and MDA-MB-436 (27.19 ± 5.57 %) cancer cells (Fig. 1b)
Summary
Breast cancer is a complex heterogeneous disease where many distinct subtypes are found. Breast cancer is a complex disease where heterogeneous cell types contribute to its initiation and progression [1, 2]. It has been broadly classified into estrogen receptor positive (ER+) and estrogen receptor negative (ER-) sub types, each of which are dependent on specific environmental cues and signaling pathways for their development [3]. Frequent diagnosis of aggressive triple negative (TN) (ER-, progesterone receptor negative (PR-) and Her Neu-) form of breast cancer in young African American (AA) women suggest disparity in development of this deadly disease [4, 5]. Even after adjustments for socio-economic factors, AA breast tumors appear to exhibit specific aggressive characteristics suggesting existence of unique biology contributed both by tumor cells and host microenvironment [8]
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