Abstract
The cyclin-dependent kinases form a large family of enzymes in human cells that are involved in the control of cell proliferation and transcription. A large number of small molecule inhibitors of this class of enzyme have been developed in both the pharmaceutical and academic communities, and at least two have entered clinical trial, having shown efficacy in preclinical models. Alterations in the activity of this class of enzymes is a frequent feature of human cancers, brought about by altered expression of either the enzymes themselves or their regulators such as p21, p27 and p16. The exact role of each of the different kinases has proved hard to determine as knockout mouse studies have implied a degree of redundancy and the exact substrates of each enzyme in vivo are still unclear. In addition, most of the current inhibitors are not specific to a single form of the enzyme and new regulatory pathways are still being discovered. Intense studies of one such inhibitor, R-Roscovitine (CYC202), including trials involving more than 100 patients, have established the potential of the class as non-genotoxic anti-cancer drugs. In some model systems the activity of this class of compound is best explained by their activity as inhibitors of transcriptional elongation, and a link between this mechanism and the induction of apoptosis has been established. The concept of cyclin-specific inhibitors as more sophisticated genetic models of target validation in this field will be discussed.
Highlights
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
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
The present article reviews results from neoadjuvant studies in which endocrine therapy was given to patients whose primary breast cancer was still within the breast so that changes in tumour volume could be used to assess clinical response and so that sequential biopsies could be taken for molecular analyses designed to identify predictive markers
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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