Regulation of cancer stem cells by p53
© BioMed Central Ltd 2008
Published: 29 August 2008
The hypothesis that cancer stem cells are responsible for the chemoresistant and metastatic phenotypes of many breast cancers has gained support using cell-sorting strategies to enrich the tumor-initiating population of cells. The mechanisms regulating the cancer stem cell pool, however, are less clear. Two recent publications suggest that loss of p53 permits expansion of presumptive cancer stem cells in mouse mammary tumors and in human breast cell lines. These results add restriction of cancer stem cells as a new tumor suppressor activity attributed to p53.
Enrichment of tumor-initiating cells in p53-deficient mammary tumor models
The recent identification and characterization of stem cells in a variety of adult tissues has led to renewed interest in the role of stem cells in cancers. Cancer stem cells are hypothesized to be a small population of cells within a tumor that are capable of self-renewal and that can undergo differentiation to generate the phenotypic heterogeneity observed in tumors. Contemporary methods for studying cancer stem cells have most often used cell surface markers to enrich the subset of cells capable of initiating a tumor upon transplantation into an appropriate host. Molecular pathways that limit expansion of the tumor-initiating cell population could be targeted to eradicate tumors.
Using mammary tumors arising spontaneously from transplants of BALB/c-Trp53 -/- mammary epithelium, Zhang and coworkers show that cells expressing markers of mouse mammary stem cells (lin-/CD29hi/CD24hi) had a greater tumor-initiating frequency . This observation was consistent among tumors with heterogeneous expression of markers for the luminal epithelium and the basal epithelium. The lin-/CD29hi/CD24hi population shared additional features of mammary stem cells, including radiation resistance and the formation of secondary mammospheres.
But how might loss of p53 lead to formation or expansion of the tumor-initiating pool? Using a unique culture model of luminal breast epithelial cells (BPEC-T), Godar and coworkers demonstrate that p53 binds to the promoter of CD44 , a commonly used marker of cancer stem cells , and represses CD44 expression. Constitutive expression of CD44 blocked p53-dependent apoptosis and rendered cells resistant to doxorubicin. Conversely, suppression of CD44 expression restricted tumor-initiating cells.
These results link the loss of p53 function to increased expression of CD44, which promotes expansion of tumor-initiating cells purified in tumors. The p53 protein appears to play a similar role in embryonic stem cells, where p53 represses expression of Nanog – which limits the pool of pluripotent cells [4, 5]. In contrast, loss of p53 extends the repopulating activity of tissue-specific stem cells [6, 7]. Disruption of BRCA1 also allows expansion of breast stem cells . The restriction of stem cells may therefore be a fundamental pathway for tumor suppression.
Reading between the cell lines
While expansion of the tumor-initiating cell population in p53-deficient mammary epithelial cells is consistent in both mouse mammary and human breast epithelial cells, the role of CD44 is not. Although loss of p53 expression resulted in increased levels of CD44 protein in BPEC-T cells and in basal mammary epithelium of Trp53 -/- mice , there was no enrichment for tumor-initiating cells within the CD44+/CD24-population in BALB/c-Trp53 -/- mammary tumors . This apparent discrepancy points to heterogeneity in the expression of markers among cancer stem cells. In mammary tumors from Brca1Δ Exon11 /Trp53+/- mice, two discrete tumor-initiating populations were identified that express either CD44+/CD24-or CD133+ . As coexpression of CD44 and CD133 was not detected in these pools of cells, it appears that CD44 is not essential for sustaining the pool of cancer stem cells.
Indeed, p53 represses expression of more than 20 target genes  that may contribute to maintenance of the pool of tumor-initiating cells. Genes such as Nanog may have direct actions in supporting self-renewal of cancer stem cells, allowing the pool to expand. Loss of p53 would also allow increased expression of the multidrug-resistance gene (ABCB1 or MDR1) that renders cells resistant to chemotherapies. Similarly, both increased proliferation and decreased apoptosis would be expected to result from de-repression of CDC25C and BIRC5/Survivin when p53 function is disrupted. CD44 may therefore be only one mechanism by which p53 may act to restrict the tumor-initiating population of cancer cells.
Cancer stem cells: puppet or puppeteer?
It is clear that that p53 plays a pivotal role in tumor suppression. Mutation and loss of function of p53 are among the most common alterations in epithelial cancers , and gene expression signatures associated with dysfunctional p53 have been shown to predict patient survival [12, 13]. The p53 protein regulates a variety of pathways (cell cycle arrest, apoptosis, DNA repair, senescence and autophagy) that can contribute to suppression of tumors. The publications by Zhang and colleagues and by Godar and colleagues now add suppression of cancer stem cells as an additional activity by which p53 can inhibit tumors [1, 2]. So which of these pathways dominate? The answer will have significant impact on therapeutic strategies.
- Zhang M, Behbod F, Atkinson RL, Landis MD, Kittrell F, Edwards D, Medina D, Tsimelzon A, Hilsenbeck S, Green JE, Michalowska AM, Rosen JM: Identification of tumor-initiating cells in a p53-null mouse model of breast cancer. Cancer Res. 2008, 68: 4674-4682. 10.1158/0008-5472.CAN-07-6353.View ArticlePubMedPubMed CentralGoogle Scholar
- Godar S, Ince TA, Bell GW, Feldser D, Donaher JL, Bergh J, Liu A, Miu K, Watnick RS, Reinhardt F, McAllister SS, Jacks T, Weinberg RA: Growth-inhibitory and tumor-suppressive functions of p53 depend on its repression of CD44 expression. Cell. 2008, 134: 62-73. 10.1016/j.cell.2008.06.006.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
- Lin T, Chao C, Saito S, Mazur SJ, Murphy ME, Appella E, Xu Y: p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol. 2005, 7: 165-171. 10.1038/ncb1211.View ArticlePubMedGoogle Scholar
- Qin H, Yu T, Qing T, Liu Y, Zhao Y, Cai J, Li J, Song Z, Qu X, Zhou P, Wu J, Ding M, Deng H: Regulation of apoptosis and differentiation by p53 in human embryonic stem cells. J Biol Chem. 2007, 282: 5842-5852. 10.1074/jbc.M610464200.View ArticlePubMedGoogle Scholar
- Dumble M, Moore L, Chambers SM, Geiger H, Van ZG, Goodell MA, Donehower LA: The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging. Blood. 2007, 109: 1736-1742. 10.1182/blood-2006-03-010413.View ArticlePubMedPubMed CentralGoogle Scholar
- Meletis K, Wirta V, Hede SM, Nister M, Lundeberg J, Frisen J: p53 suppresses the self-renewal of adult neural stem cells. Development. 2006, 133: 363-369. 10.1242/dev.02208.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
- 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
- Riley T, Sontag E, Chen P, Levine A: Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol. 2008, 9: 402-412. 10.1038/nrm2395.View ArticlePubMedGoogle Scholar
- Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, et al: The genomic landscapes of human breast and colorectal cancers. Science. 2007, 318: 1108-1113. 10.1126/science.1145720.View ArticlePubMedGoogle Scholar
- Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A, Pawitan Y, Hall P, Klaar S, Liu ET, Bergh J: An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci USA. 2005, 102: 13550-13555. 10.1073/pnas.0506230102.View ArticlePubMedPubMed CentralGoogle Scholar
- Troester MA, Herschkowitz JI, Oh DS, He X, Hoadley KA, Barbier CS, Perou CM: Gene expression patterns associated with p53 status in breast cancer. BMC Cancer. 2006, 6: 276-10.1186/1471-2407-6-276.View ArticlePubMedPubMed CentralGoogle Scholar
- Langerod A, Zhao H, Borgan O, Nesland JM, Bukholm IR, Ikdahl T, Karesen R, Borresen-Dale AL, Jeffrey SS: TP53 mutation status and gene expression profiles are powerful prognostic markers of breast cancer. Breast Cancer Res. 2007, 9: R30-10.1186/bcr1675.View ArticlePubMedPubMed CentralGoogle Scholar
- Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, Rasmussen KE, Jones LP, Assefnia S, Chandrasekharan S, Backlund MG, Yin Y, Khramtsov AI, Bastein R, Quackenbush J, Glazer RI, Brown PH, Green JE, Kopelovich L, Furth PA, Palazzo JP, Olopade OI, Bernard PS, Churchill GA, Van DT, Perou CM: Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol. 2007, 8: R76-10.1186/gb-2007-8-5-r76.View ArticlePubMedPubMed CentralGoogle Scholar