Cancer stem cell heterogeneity in hereditary breast cancer
© BioMed Central Ltd 2008
Published: 16 April 2008
The cancer stem cell hypothesis proposes that tumors arise in stem or progenitor cells generating in tumors driven by a subcomponent that retains cancer stem cell properties. Recent evidence supports the hypothesis that the BRCA1 gene involved in hereditary breast cancer plays a role in breast stem cell function. Furthermore, studies using mouse BRCA1 knockout models provide evidence for the existence of heterogeneous cancer stem cell populations in tumors generated in these mice. Although these populations may arise from different stem/progenitor cells, they share the expression of a common set of stem cell regulatory genes and show similar characteristics in in vitro mammosphere assays and xenograft models. Furthermore, these 'cancer stem cells' display resistance to chemotherapeutic agents. These studies suggest that breast tumors may display intertumor stem cell heterogeneity. Despite this heterogeneity, cancer stem cells may share common characteristics that can be used for their identification and for therapeutic targeting.
In a recent publication, Wright and colleagues  used a mouse knockout model of BRCA1 to demonstrate cellular heterogeneity of cancer stem cells. They generated 16 cell lines from five independent BRCA1Δexon 11/p53+/- mouse mammary tumors. They then examined the expression of cell-surface markers associated with cancer stem cells in these cell lines. Interestingly, cells derived from one tumor contained populations that were characterized as CD44+/CD24- and that displayed stem cell properties, whereas cells derived from another tumor contained a cancer stem cell population that was characterized by CD133 expression. The CD44+/CD24- phenotype previously has been described as identifying a cell population with stem cell properties in human breast tumors .
Sheridan and colleagues  recently reported that a number of basal mammary carcinoma cell lines contain a CD44+/CD24- cell population, whereas luminal cell lines do not. In contrast to human cancer cells, normal mouse mammary stem cells have been reported to have a CD24+ phenotype . Although CD133 previously has not been reported to be expressed on breast cancer stem cells, this marker is expressed on a variety of other human cancer stem cells, including those of the brain, prostate, and pancreas. Interestingly, Wright and colleagues  found no overlap between the CD44+/CD24- and the CD133+ cell populations. This suggests that there may be heterogeneity within stem cell populations in BRCA1 tumors. As has previously been proposed for sporadic breast tumors, this heterogeneity may potentially result from different cells of origin .
The cancer stem cell hypothesis proposes that tumors arise in either normal stem or progenitor cells through the disregulation of self-renewal processes. This results in tumors that are driven by a cellular subcomponent that retains stem cell properties. Recently, our group reported that BRCA1 functions as a regulator of breast stem cell fate . This suggests the possibility that the heterogeneity of stem cells reported by Wright and colleagues represents different cells of origin in tumors that contain CD44+/CD24- stem cells and those that contain CD133+ stem cells. Despite the fact that there was no overlap in expression of CD44+/CD24- and CD133+ cell populations in these cell lines, both cancer stem cell populations overexpressed the stem cell genes Oct4, Notch1, ALDH1, Fgfr1, and Sox1. This is consistent with our recent report that ALDH1 is a marker of both normal and malignant human mammary stem cells . Furthermore, this suggests that a common set of 'stemness' genes may be shared between heterogeneous populations of cancer stem cells.
Wright and colleagues used both in vitro assays as well as xenograft models to demonstrate the stem cell properties of the CD44+/CD24- and CD133+ cell populations. Both of these populations form mammospheres in vitro, a characteristic shared by normal  and malignant  mammary stem cells. Interestingly, cells cultured as mammospheres or those with stem cell markers show resistance to chemotherapeutic agents such as cisplatin compared with the bulk of the cell population. The resistance of breast cancer stem cells to both radiation  and chemotherapy  has also been reported by other investigators. In addition, the proportion of cells characterized as CD44+/CD24low significantly increases following neoadjuvant chemotherapy in patients with breast cancer , demonstrating the clinical relevance of these concepts. Although transporters such as BCRP are overexpressed in some stem cells , Wright and colleagues  did not find an increase in expression of ABC transporters in either stem cell population. Thus, the mechanisms of drug resistance in these cells remains to be elucidated. Other potential mechanisms of chemoresistance of cancer stem cells include overexpression of chemotherapy metabolizing enzymes such as aldehyde dehydrogenase 1, changes in cell cycle kinetics, and over-expression of anti-apoptotic proteins .
A number of therapeutic approaches are being developed to therapeutically target breast cancer stem cells. Wright and colleagues demonstrate that the HSP90 inhibitor 17-DMAG sensitizes these cells to chemotherapy. These in vitro experiments have potential clinical implications since HSP90 inhibitors are currently in clinical trials. Furthermore, these studies indicate the feasibility of using in vitro mammosphere assays for the screening of compounds that are able to target cancer stem cells.
In summary, recent studies suggest that both hereditary and sporadic breast tumors may originate through the disregulation of self-renewal pathways in normal mammary stem and/or progenitor cells. The resulting tumors may be driven by heterogeneous populations of cancer stem cells. This heterogeneity may reflect different cells of origin and/or different mutation profiles in these cells. These heterogeneous cancer stem cell populations, in turn, may determine the overall molecular phenotype of tumors as assessed by molecular profiling. The development of suitable in vitro and mouse models should accelerate research aimed at identifying these diverse cancer stem cell populations. This should facilitate the identification of suitable targets for the development of strategies aimed at cancer prevention and therapy.
- Wright MH, Calcagno AM, Salcido CD, Carlson MD, Ambudkar SV, Varticovski L: Brca1 breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics. Breast Cancer Res. 2008, 10: R10-10.1186/bcr1855.View ArticlePubMedPubMed CentralGoogle Scholar
- Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003, 100: 3983-3988. 10.1073/pnas.0530291100.View ArticlePubMedPubMed CentralGoogle Scholar
- Sheridan C, Kishimoto H, Fuchs RK, Mehrotra S, Bhat-Nakshatri P, Turner CH, Goulet R, Badve S, Nakshatri H: CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res. 2006, 8: R59-10.1186/bcr1610.View ArticlePubMedPubMed CentralGoogle Scholar
- Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, Wu L, Lindeman GJ, Visvader JE: Generation of a functional mammary gland from a single stem cell. Nature. 2006, 439: 84-88. 10.1038/nature04372.View ArticlePubMedGoogle Scholar
- Dontu G, El-Ashry D, Wicha MS: Breast cancer, stem/progenitor cells and the estrogen receptor. Trends Endocrinol Metab. 2004, 15: 193-197. 10.1016/j.tem.2004.05.011.View ArticlePubMedGoogle Scholar
- Liu S, Ginestier C, Charafe-Jauffret E, Foco H, Kleer CG, Merajver SD, Dontu G, Wicha MS: BRCA1 regulates human mammary stem/progenitor cell fate. Proc Natl Acad Sci USA. 2008, 105: 1680-1685. 10.1073/pnas.0711613105.View ArticlePubMedPubMed CentralGoogle Scholar
- Ginestier C, Hur M, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G: ALDH1 is a marker of normal and malignant breast stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007, 1: 555-567. 10.1016/j.stem.2007.08.014.View ArticlePubMedPubMed CentralGoogle Scholar
- Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, Wicha MS: In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 2003, 17: 1253-1270. 10.1101/gad.1061803.View ArticlePubMedPubMed CentralGoogle Scholar
- Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, Pilotti S, Pierotti MA, Daidone MG: Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 2005, 65: 5506-5511. 10.1158/0008-5472.CAN-05-0626.View ArticlePubMedGoogle Scholar
- Phillips TM, McBride WH, Pajonk F: The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst. 2006, 98: 1777-1785.View ArticlePubMedGoogle Scholar
- Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J, Song E: let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007, 131: 1109-1123. 10.1016/j.cell.2007.10.054.View ArticlePubMedGoogle Scholar
- Kim M, Turnquist H, Jackson J, Sgagias M, Yan Y, Gong M, Dean M, Sharp JG, Cowan K: The multidrug resistance transporter ABCG2 (breast cancer resistance protein 1) effluxes Hoechst 33342 and is overexpressed in hematopoietic stem cells. Clin Cancer Res. 2002, 8: 22-28.PubMedGoogle Scholar
- Korkaya H, Wicha MS: Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs. 2007, 21: 299-310. 10.2165/00063030-200721050-00002.View ArticlePubMedGoogle Scholar