Abstract
Estrogen is implicated as an important factor in stimulating breast cancer cell proliferation, and presence of estrogen receptor (ER) is an indication of a good prognosis in breast cancer patients. Mcl-1 is an anti-apoptotic Bcl-2 family member that is often over expressed in breast tumors, correlating with poor survival. In breast cancer, it was been previously shown that epidermal growth factor receptors up-regulate Mcl-1 but the role of estrogen in increasing Mcl-1 expression was unknown. In ERα positive cell lines MCF-7 and ZR-75, estrogen treatment increased Mcl-1 expression at both the protein and mRNA level. In two ERα negative cell lines, SK-BR-3 and MDA-MB-231, estrogen failed to increase in Mcl-1 protein expression. We found that ERα antagonists decreased estrogen mediated Mcl-1 expression at both the protein and mRNA level. Upon knockdown of ERα, Mcl-1 mRNA expression after estrogen treatment was also decreased. We also found that ERα binds to the Mcl-1 promoter at a region upstream of the translation start site containing a half ERE site. Streptavidin-pull down assay showed that both ERα and transcription factor Sp1 bind to this region. These results suggest that estrogen is involved in regulating Mcl-1 expression specifically through a mechanism involving ERα.
Highlights
Estrogen has been implicated as an important factor in stimulating breast cancer proliferation and cell survival [1]
We found that mRNA expression increased approximately 1.5-fold in both MCF-7 and ZR-75 cells after 6 hours of estrogen treatment, (Figure 1 A,B) and increased 2-fold in both MCF-7 and ZR-75 cells after 24-hours after estrogen treatment (Figure 1 A, B)
We found that mRNA levels increased to 2 fold at 10 nM estrogen treatment after six hours
Summary
Estrogen has been implicated as an important factor in stimulating breast cancer proliferation and cell survival [1]. Presence of estrogen receptor alpha (ERa) is an indication of a good prognosis and ERa positive patients are often treated with hormonal therapy [1]. ERa positive breast cancer patients are treated with anti-estrogen hormonal therapies such as the drugs Tamoxifen [2]. Tamoxifen antagonizes ERa by binding and inhibiting estrogeninduced activation of transcription [2]. This inhibition occurs through the blockage of activation function (AF) 2 sites on ERa. This inhibition occurs through the blockage of activation function (AF) 2 sites on ERa This leaves AF1 sites unaffected creating a potential mechanism for drug resistance [2]. Understanding how estrogen contributes to drug resistance will be important in developing new strategies to treat ER a positive breast cancer
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