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Sirtuin 3 as a mediator of mitochondrial function upon estradiol treatment in hormone- dependent breast cancer cells

Breast cancer is the most frequent cancer among women, and 70% of all breast cancer cases are estrogen receptor (ER) positive. Sirtuin 3 (Sirt3) has a promising role in cancer tumorigenesis and treatment, but there have been controversies about its role as oncogene or tumor suppressor in different types of cancer. We have recently shown that de novo expressed Sirt3 in ER-α positive MCF-7 breast cancer cells causes higher expression of ER-α, but lowers tumorigenic properties of the cells. Therefore, we proposed that Sirt3/ER-α crosstalk may be responsible for the reduction of proliferation and invasiveness of MCF-7 cells. To investigate this crosstalk in estrogen (E2)-responsive MCF-7 cells, we are using combination of treatments (E2 and its antagonist, ICI), overexpressed Sirt3 and Sirt3 siRNA transfection to alter the expression and activity of different proteins (involved in mitochondrial biogenesis, metabolic regulation, cell cycle progression). We hypothesise that this crosslink is happening via proteins which are being activated in mitochondria and then translocated to nucleus. So far we observed that E2 addition induced metabolic activity and increased gene and protein ER-α level in control MCF-7, whereas Sirt3 siRNA suppressed ER-α protein level. In control MCF-7 cells E2 increases and ICI abolishes ADP/ATP ratio. In Sirt3 clones, the addition of E2 increases mtROS levels, without affecting ADP/ATP ratio, suggesting that, despite of proliferative effect of E2, Sirt3 clones still retain their OXPHOS fuction (aerobic respiration). Furthermore, we are testing intracellular distribution of ER-α and potential Sirt3 targets under different treatments by using cellular fractionation and confocal microscopy. Successful completion of these experiments will contribute to mechanistic understanding of the role of Sirt3 in hormone-dependent breast cancer cells, as a potential pharmacological target.

sirtuin 3 ; breast cancer ; estradiol ; mitochondria

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