BackgroundThe process by which breast cancer stem cells arise is unknown. It may be that the benign stem cells in breast tissue are transformed into malignant stem cells through the acquisition of genetic abnormalities. In this study, we collected and compared benign and malignant breast stem/progenitor cells to determine whether specific genetic abnormalities occur in breast cancer stem/progenitor cells within the human body.MethodsFresh surgical specimens from benign and malignant breast tissues were obtained directly from the operating room and examined. Cells variably expressing stem cell-associated surface markers CD49f and CD24 were collected by fluorescence-activated cell sorting. The frequencies of these cells in benign and malignant breast tissues were ascertained. Oncogenetic mutation analyses were performed and expression of stem cell-associated genes was measured.ResultsThe frequencies of stem/progenitor cells were similar between benign and malignant tissues. Stem cell-associated gene expression also was similar between benign and malignant stem cells. Genetic mutations in the PIK/AKT pathway were found in 73% of the tumors’ stem cells, specifically within two subpopulations. No mutations were found in stem/progenitor cell subpopulations from benign breast tissue.ConclusionsThe results of this study suggest that, following malignant transformation, breast cancer stem/progenitor cells retain their stem cell functions and relative frequencies. In addition, they develop malignant capabilities by acquiring mutations in genes critical for maintaining normal cellular metabolism and proliferation.Electronic supplementary materialThe online version of this article (doi:10.1245/s10434-011-1892-z) contains supplementary material, which is available to authorized users.
Background: In-vitro model systems provide an important tool in breast cancer research and, over recent years, there have been considerable advances in their construction. However, despite these advances, the majority of models still employ a narrow range of established cell lines, which frequently are not appropriate for the in-vivo cell type they are representing1. Method: As part of the Breast Cancer Campaign Tissue Bank, we have developed a cell culture programme which feeds into the main tissue collection and involves the systematic generation of materials from normal, high-risk, cancer-containing and malignant breast tissue in order to make available a breadth of material to the research community. Following informed patient consent, fresh tissue is retrieved and, using tissue digestion and magnetic bead technology2, purified cell populations are isolated, characterized and frozen down, or further processed for DNA and RNA isolation. Results: We have isolated purified populations of luminal epithelial, myoepithelial and fibroblast cells from normal breast, risk-reduction (BRCA1 and BRCA2 mutated) breast and from morphologically normal breast tissue surrounding breast cancer. We have generated matched surround and tumour-associated fibroblasts, as well as matched tumour epithelial and tumour-associated fibroblast cell isolates. These cells have been incorporated into 2- and 3-D culture models and we have demonstrated successful genetic manipulation, with siRNA gene knockdown and gene over-expression through retroviral transduction. Immortalisation of selected cell populations is currently underway. Intact organoids and tissue explants have also been generated for in-vitro experimentation. Matched frozen and FFPE samples are available, together with full clinicopathological data. The research community can access these biomaterials via a web-based search portal, with full user support. Conclusion: Through this cell culture programme we aim to make available a wider and more appropriate range of materials for breast research, which should allow more clinically relevant model systems to be developed and add value to breast cancer biobanking. References: 1. Thompson A., et al. Evaluation of the current knowledge limitations in breast cancer research: a gap analysis. Breast Cancer Research 2008; 10: R26. 2. Gomm J.J. et al. Isolation of pure populations of epithelial and myoepithelial cells from the normal human mammary gland using immunomagnetic separation with Dynabeads. Analytical Biochemistry 1995; 226: 91-99. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-19-05.
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