Altered signaling in anti-estrogen-resistant human breast cancer cells
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KeywordsResistant Cell Wortmannin Human Breast Cancer Cell Line Resistant Cell Line Estrogen Receptor Expression
Breast cancer patients with advanced disease often benefit from endocrine therapy. However, many patients develop acquired resistance to treatment after a period of response. In the Department of Tumor Endocrinology we have established several human breast cancer cell lines with acquired anti-estrogen resistance through long-term treatment with different anti-estrogens. These cell lines have been used for our studies of the signaling pathways, which may be activated in cells with acquired anti-estrogen resistance.
Analysis of the expression of genes known to be important for human breast cancer has revealed that the majority of the anti-estrogen-resistant breast cancer cell lines have decreased estrogen receptor expression and signaling. However, increased expression of phosphorylated PKB/Akt (p-Akt) and Akt kinase activity was observed in several anti-estrogen-resistant cell lines. The PI3 kinase is an upstream signaling molecule for Akt, and inhibition of PI3-kinase activity with wortmannin or LY294002 deceases the level of p-Akt. Both PI3-kinase inhibitors inhibited growth of the resistant cells. However, wortmannin displayed a more profound growth inhibitory effect on anti-estrogen-resistant cell lines than on parental MCF-7 cells. Treatment with the novel Akt inhibitor SH-6 resulted in a very strong growth inhibition of three resistant cell lines overexpressing p-Akt, whereas the parental MCF-7 cells were significantly less growth inhibited.
It was investigated whether the increased level of p-Akt in the resistant cells was due to signaling from IGF-IR and IRS-1, or whether it resulted from decreased PTEN activity. Both involvement of IGF-IR and PTEN could be excluded.
At present, our working hypothesis is that anti-estrogen-resistant human breast cancer cell lines with an increased p-Akt level require signaling via activated Akt to survive and maintain growth in the presence of the anti-estrogen. Studies on clinical material will be important to evaluate whether anti-estrogen-resistant tumors overexpress p-Akt and whether Akt may be a target for treatment of anti-estrogen-resistant breast cancer.