Abstract
It is generally believed that tumours originate from adult tissues, in which most cells are quiescent, and that the proliferative advantage of tumour cells arises from their ability to bypass senescence. Once this is obtained, cells can accumulate further genetic alterations that drive progressive transformation into highly malignant derivatives. How normal cells evade the senescence program remains an unresolved issue. Recent findings suggest the alternative possibility that stem/progenitor cells are the targets of transformation. Many tumours contain only a small subset of cells endowed with the property of uncontrolled growth (cancer stem cells). Although the program of senescence in stem cells is suppressed, their lifespan is restrained by signalling pathways (p19-p53; p16-Rb) that are activated by DNA damage (telomere dysfunction, environmental stresses). It is proposed that inactivation of these pathways in stem cells might contribute to tumour formation. We set out to cultivate in vitro breast stem cells from the mouse mammary gland (BSC) based on their ability to survive in suspension as 'mammospheres' and to differentiate into myoepithelial and epithelial cells. Murine mammospheres do not result from passive cell aggregation and have clonal origin, as assessed by labelling cell membranes with different epifluorescent dyes. To prove the 'staminality' of these cellular populations we performed in vivo reconstitution experiments, by inoculating single cell suspensions of mammospheres in the mouse cleared fat pad. Using the same experimental approach, we were also able to generate mammospheres from MMTV-ErbB2(cNeu) transgenic mice. These mice develop polyclonal mammary adenocarcinomas arising synchronously. The mammospheres arising from MMTV-ErbB2 mice show a dramatically prolonged lifespan upon serial passages and are bigger than their normal counterparts (more than 1000 cells/sphere vs 200–400 cells in the w.t. mice). To prove that cancer mammospheres are enriched in cancer BSC, we are performing transplantation experiments in which single cell suspensions of these mammospheres are inoculated in the normal gland of singenic mice.
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
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
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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