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Altered signaling in anti-estrogen-resistant human breast cancer cells

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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.

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Lykkesfeldt, A., Frogne, T., Jepsen, J. et al. Altered signaling in anti-estrogen-resistant human breast cancer cells. Breast Cancer Res 7, P4.03 (2005) doi:10.1186/bcr1133

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Keywords

  • Resistant Cell
  • Wortmannin
  • Human Breast Cancer Cell Line
  • Resistant Cell Line
  • Estrogen Receptor Expression