Abstract
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.
Highlights
We have shown that overexpression of TGF-β1 in mammary epithelial cells suppresses the development of carcinomas and that expression of a dominant negative type II TGF-β receptor (DNIIR) in mammary epithelial cells under control of the MMTV promoter/enhancer increases the incidence of erbB2 in carcinomas accompanied by Tgfbr2fspKO fibroblasts
We found that the frequency of the IVS10-6T>G is characterized by multiple physiologic abnormalities, including mutation was not increased in breast cancer cases as compared with neurodegeneration, immunologic abnormalities, cancer predisposition, controls
We examined the incidence of tumors the hypothesis that Single nucleotide polymorphisms (SNPs) in the regulatory regions of genes that create formed in these ERα knockout mice bearing the Wnt-1 transgene
Summary
Endocrine therapy for breast cancer is a major modality for the treatment of breast cancer, producing response rates between 30% and 40% of unselected patients with the minimum of toxicity. Several human genetic diseases are known to be or suspected to be due to defects in DNA repair or cell cycle control Some of these patients are radiation sensitive and/or predisposed for cancer as a cause of mutations in genes involved in these cellular pathways. Microarray-based comparative genomic hybridization (arrayCGH) allows the construction of high-resolution genome-wide maps of copy number alterations, and statistical software packages are available for exploring and analysing array-CGH data (see, for example, [2,3]), facilitating the delineation of the boundaries of CNAs in individual tumors and thereby localizing and identifying potential oncogenes and tumor suppressor genes. The aim of this study was to evaluate the prognostic value of gene expression-based classification as well as established prognostic markers, including mutation status of the TP53 gene, in a group of breast cancer patients with long-term (>10 years) fol The aim of this study was to compare MR spectroscopic findings from breast cancer tissue with histological grading of tumor and patient lymph node status
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