147
R eview Ar ticle
ABSTRACT
Cancer is fundamentally a cellular genetic disease capable of transferring the “disease” to the next generation of mutated cells. Similar proliferative and information transferring capacity exists in the stem cells of various organ systems in the human body. Understanding the bio-mechanism of stem cell metabolism and its regulation by signaling molecules and extracellular micro- environment is an important step toward successful prevention and treatment of cancer. According to the cancer stem cell hypothesis, both hereditary and sporadic cancers can arise from deregulation of these cancer stem cells (CSCs), triggered by genetic and environmental factors. It is shown that deregulation of normal self-renewal pathways in undifferentiated breast stem cells or progenitor cells had altered mammary system or progenitor cells, resulting in abnormally differentiated cells in human and rodent breast cancer cell lines.Breakthroughs in molecular pathways have important therapeutic implications. Hence, signifi cant stress is laid on targeting signaling molecules and their micromilieu in breast cancer therapy.
KEY WORDS: Cancer, molecular pathways, progenitor cell, stem cell, targeted therapy
Review of stem cell deregulation and breast cancer:
An emerging hypothesis
Darnal Hari Kumar1, Methil Kannan Kutty
Pathology, Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, Kuala Lumpur, Malaysia, 1Pathology, Monash University Sunway campus, Johor Bahru, Malaysia
Address for correspondence to: Dr. Hari Kumar Darnal, Professor of Pathology, Monash University Sunway Campus, Clinical school Johor Bahru-80100 Johor Bahru Malaysia, E-mail: [email protected]
INTRODUCTION
The regenerative capacity of human body is known for ages but thought to be of limited ability. Rejuvenation medicine is mentioned in Ayurvedic literature which applies its anti-aging and detoxification therapy even to this day. It is shown that deregulation of normal self-renewal pathways in undifferentiated breast stem cells or progenitor cells had altered mammary system or progenitor cells, resulting in abnormally differentiated cells in human and rodent breast cancer cell lines.[1,2] The pluripotency and plasticity of the murine stem cells and its molecular pathways were known to marine biologists much earlier[3] than the first human in vitro embryonic stem cell culture in 1998.[4] The basic attributes of the stem cells are its capacity for self-renewal, proliferation, differentiation allowing survival of stem cell population with original DNA template, and differentiation of diverse types of mature cells to replace aging cells in the adult tissue. [5] The total population of stem cells is tightly regulated by both intrinsic and extrinsic mechanisms, stabilizing a stable stem cell pool with an effective specific regulatory mechanism to self- renew, differentiate, prolong proliferative potential, and repress premature senescence and apoptosis.[4-9]
In contrast, the adult cells have somewhat limited plasticity, self-renewal, and self- maintenance (Hayflick effect) related to telomere shortening.[10-12] According to Cairn’s hypothesis,[13] these stem cells are divided into two distinct populations of cells: stem cells with slow cell cycle and transit amplifying cell (TAC) with faster cell cycle with proliferative and clonogenic capacity.[12-15] Adult stem cell plasticity was demonstrated
in both hematopoietic[16] and stromal stem cells[17] in the bone marrow culture, which can be manipulated to generate various products that can be used in various clinical disease conditions. Further, these stem cells were found to trigger regeneration of the damaged tissues in the infarcted myocardium. [18,19] It is interesting to note that similar pleuripotent stem cells highly similar to embryonic stem cells can be generated by the delivery of three genes (Oct4, Sox2, and Klf4) to the differentiated cells.[20,21] It is believed that reprogramming of these “induced pleuripotent stem cells”
(iPS) may obliterate the need of ESC for the clinical use in future.[22,23]
Objective
The objective of the micro-review article is to comprehend the basic concept of stem cell biology based on the latest research findings and try to correlate its implication in breast cancer development, prevention, and treatment.
MOLECULAR CONTROL OF STEM CELL BEHAVIOR
It is still not clearly known how stem cell activities are controlled by different
Access this article online Website: www.ijpmonline.org PMID: xxxxxxxxx (when available) DOI: 10.4103/0377-4929.97842 Quick Response Code:
148
genetic molecular factors. However, three factors have emerged to be of utmost importance. These are (1) local cellular component, (2) local micro-environmental factors, and (3) local extracellular matrix component. It is realized that these components interact with each other via cytokines, cell adhesion molecules like cadherin–catenin molecules, bone morphogenetic protein (BMP), and other signaling gene products like APC, PTEN, Wnt, Notch, and sonic hedgehog (SHH).[24-30] Thus, it is important to realize that there are plenty of checks and balances at molecular level to maintain normal proliferation of stem cell population.
The normal somatic stem cells (NSSCs) in the tissues have slow cell turnover rate, and thus maintain its genomic stability. NSSC is highly clonogenic and found to be chemoresistant, attributed to the presence of detoxifying enzymes like ATP membrane pump genes, DNA mismatch repair genes, and various membrane protein molecules like Nestin4 and musaeli 1, beta-1 integrin and collagen V receptor binding molecules,[31-33] which may help release of chemotherapeutics from the cells.
BREAST CANCER STEM CELL
A paradigm shift had occurred in our conceptual approach to oncogenesis following the advent of the cancer stem cell hypothesis.[34] Recent researches suggest that breast cancer stem cell (BCSC)s may be the mutated counterpart of NSSCs which have retained the survival capacity.[31,32] Since most of the tumors are heterogeneous [composed of terminally differentiated cells, partially proliferating TAC, and proliferating cancer stem cells (CSCs)], it is believed that these CSCs are capable of transferring the disease. Therefore, it is likely that relapses occur from these surviving CSCs.[32] Search for such targets led to the discovery of markers of these CSCs (CD44 and CD133). Researchers have shown the capacity of CD34+/CD38 AML cells to transfer leukemia in NOD/SCID mice. [30] Similarly CD44+ESA+CD24/
low fraction of breast cancer cell transfer[31] and CD133+ cell identified as clonogenic stem cells in breast and CNS[32] have been reported. Therefore, eradiation of these stem cells has become the target of chemotherapy.[32-34]
ALDH is found to be a marker of stem/progenitor cells of the normal human breast and breast carcinomas. ALDH1 expression marker can detect normal and malignant stem/progenitor cells;
this further fortifies the cancer stem cell hypothesis. Moreover, ALDH1 expression aids analysis of cancer initiation and progressive transition from the normal to the pre-malignant and then to the malignant state. ALDH1 expression is found to be a potent predictive factor for breast cancer, having direct or inverse link with tumor grade, ER/PR status, ERBB2 overexpression, and basal-like cytokeratins (CK 5/6 and CK14).[35]
Cell of Origin of Breast Cancer
As the cells of origin and mechanisms that support tumor heterogeneity in breast cancer are not clear, it promoted investigators to examine three mouse models of mammary tumorigenesis (MMTV-wnt-1, MMTV-neu, and P53+/-) for changes
in their epithelial cell hierarchy through the preneoplastic and neoplastic phases of tumor development. In preneoplastic tissue, only MMTV-wnt-1 mice showed changes that signified that wnt-1 activation which induces the appearance of aberrant progenitor cells, suggesting that both mammary stem and progenitor cells can serve as the cellular targets of wnt-1 induced tumorigenesis. In MMTV-wnt-1 tumors, the luminal epithelial progenitor marker CD61/3 integrin detected an extremely tumorigenic CSC population compared with the CD61- subset, while CD61 expression also defined a CSC subset in 50% of p53+/- derived tumors. CSCs were inconspicuous in the more homogenous MMTV-neu/erbB2 model, indicating a different form of tumorigenesis. These findings by Francosis et al.[36]
tend to support the value of the progenitor marker CD61 in the identification of CSCs that sustain specific mammary tumors.
Cancer treatment modalities based on tumor regression may have led to generation of agents which are lethal exclusively to differentiated tumor cells without any effect on the small CSC population.[37] Thus, the emergence of more successful cancer therapies may focus on this important CSC population.
And obviously, the success of these new strategies depends on comprehensive studies of all the properties of CSCs. Recently, the phenotype of the mouse mammary stem cells (MaSCs) was identified by several groups.[38]
Signaling Pathways in Breast Cancer
It is interesting to note that the same self-renewal pathways involved in normal stem cell development have been found in the development of mammary gland. These include epidermal growth factors, Wnt and SHH pathways, transcription factor B lymphoma MoMLV (Bmi 1), and Notch receptor pathway in the development of human ductal carcinoma in situ (DCIS) mammospheres from CSCs. [39,40] Further, it is found that human breast tumors contain a BCSC population with properties suggestive of normal stem cells. Shimono et al.[40] reported that three clusters – miR- 200c-141, miR-200b-200a-429, and miR-183-96-182 – were downregulated in human BCSCs, normal human and murine mammary stem/progenitor cells, and embryonal carcinoma cells.
miR-200c modulated the expression of BM11, a regulator of stem cell self-renewal, and repressed the clonal extension of breast cancer cells and suppressed the growth of embryonal carcinoma cells in vitro. Further, miR-200c robustly repressed not only the development of mammary ducts from normal MaSCs but also tumorigenesis determined by human BCSCs in vivo. The synchronized downregulation of three microRNA clusters and the similar functional regulation of clonal expansion by miR-200c present a molecular link between BCSCs with normal stem cells, as reported by Yohei Shimono et al.[40]
Mammary tumors induced by the Wnt signaling pathway[41]
contain various cell types and express early developmental markers. Expression of the Wnt-1 proto-oncogene in mammary glands of transgenic mice propagates epithelial cells bearing progenitor cell markers and the succeeding tumors have these markers and contain luminal epithelial and myoepithelial
149
tumor cells with secondary mutation, loss of PTEN, indicative of their origin from a common progenitor. Mammary tumors in transgenic mice expressing -catenin and c-myc, downstream components of the Wnt signaling pathway, also contain a good number of myoepithelial cells and cells expressing keratin 6. MaSCs and/or progenitor to mammary luminal epithelial and myoepithelial cells may be the target for oncogenesis by Wnt-1 signaling elements. Wnt pathway activation may be an early provocative event in multistep carcinogenesis. Thus, the developmental diversity of different breast cancers is partly due to the different effects of oncogenes on diverse cell types in the breast.[41]
Yet another aspect that merits mention here is the finding of overexpression of Bmi1 in several breast cancer cell lines and post-selection human MECs immortalized with human papilloma virus E6 oncogene which abrogates the p53/p21waf pathway.[42] Dimri et al. (2002)[42] implicate Bmil involvement in immortalization. Overexpression of Bmil in post-selection MECs immortalizes them, circumventing senescence, and this is coupled with induction of telomerase activity which is probably mediated by a mechanism; this implicates Bmi1 activity via RING finger as well as the conserved helix-turn-helix domain, thus Bmil directly or indirectly regulates telomerase expression in MECs and might have a role to play in the development of human breast cancer.[43] In this context, a brief reference to the study by Paola Rizzo et al.[44] deserves mention, which showed that in breast cancer cell lines, there was not only lack of correlation between Notch-induced transcriptional activity and Notch receptor levels, but also Notch-induced transcriptional activity peaked in estrogen receptor A negative (ERA), Her2/neu non-overexpressing cells.
In estrogen receptor A positive (ERA+) cells, estradiol repressed Notch activity and Notch-1 IC nuclear levels, and affected Notch-1 cellular distribution. This study indicated the potential efficacy of combined antiestrogens and Notch inhibitors (gamma secretase inhibitor or GSI) in ERA+ breast cancers; it also lends support to Notch signaling as a prospective therapeutic target in ERA breast cancers.
Mammary Stem Cell Identifi cation
These are a population of quiescent, self-renewing cells lying along the basement membrane of terminal duct lobular units underneath the epithelial/luminal cells. These cells have been identified by various studies and are found to be capable of differentiating into ductal, alveolar, and myoepithelial cells by non-adherent mammosphere culture, labeling by 5-bromo-2 deoxy-uridine and cell surface marker-sca1, CD49f, and also by Hoechst dye efflux study.[28-32] Elgene Lim et al. recently (2010) [45] discovered four mouse mammary cell subpopulations that exhibited distinct gene signatures. These signatures, when compared with the molecular profiles of different mouse models of mammary tumorigenesis, uncovered that tumors from MMTV-wnt-1 and P53-/- mice were enriched with mammary stem cell subset genes (MASC), but the gene profiles of MMTV-neu and MMTV-pyMT tumors were most consistent with the luminal progenitor cell signature. The mouse mammary epithelial cell signatures compared with their
human counterparts showed considerable preservation of genes with prominence of conserved pathways in the three epithelia subsets. Many of the conserved genes in the MSC population strikingly conformed to epithelial–mesenchymal transition (EMT) signature genes, implying that these in tumor cells could be a sign of basal epithelial cells. Comparative analysis of normal mouse epithelial subsets with murine tumor models has implicated distinct cell types in contributing to tumorigenesis in the different models. The implications of these studies suggest that tumors can originate from these MaSCs/progenitor cells as result of deregulation of regulated self-renewal processes due to accumulation of genetic mutations induced by environmental and genetic factors. It is also possible that both hereditary and sporadic breast cancers may develop through deregulation of similar pathways in mature and precursor cells as suggested by global DNA copy number aberration and gene expression profile study of 359 breast tumors.[43] [Figure 1]. Thus, these pathways may be the possible target for prevention and curative therapy in future. [42,44,45] There are, however, many issues to look into before such therapy can be instituted judiciously and effectively. At this point, it must be mentioned that there is no exact correlation of histological variants of breast carcinomas with the molecular and DNA profile. It may due to difference in technologies used, or technology used may not be sophisticated, or more time and research is needed to know the exact correlation.
Mammary Niche and Signals
Specialized microenvironments around these stem cells are important factors which control the behavior of these adult stem cells. Mammary fat pad study has shown that reproductive hormones control the stem cell activation through hormone- positive cells, which induces paracrine signals leading to
Dysregularion/
mutations mutation
BCSC
Normal pathway
Dedifferentiatio n pathways?
Basal- Luminal
simple Luminal
complex Modifier Mixed
ER +
Best prognosis EMT +
BRCA 1 +
Poor
BRCA2+
L-B+
ER+/- Intermedi ate
Luminal b and complex subtype Intrinsic genes +
DNA CNA losses Intrinsic gene Expression HER-2
Progenitor/
precursor
Worst prognosis
Herceptin
CSC NSC Normal
cell
Figure 1: Proposed molecular origin of breast cancer based on global DNA copy number aberra on and gene expression profi le
150
activation of stem cells via amphiregulin and RANKL pathway, especially in breast. Involvement of Notch and Wnt pathways has also been reported,[26,27] which will be elaborated briefly subsequently.
Steroid Hormone and Breast Stem Cell
Steroid hormones are known to act in a paracrine fashion in the mammary gland at a specific period of life, delegating different functions to locally produced factors.[31] Thus, changing pattern of hormones in the body can modify cell–cell interaction for morphogenesis and differentiation. Excessive/deregulated hormonal signals may change the MaSCs and their niches, and may lead to dysregulated early events in breast carcinogenesis as shown by Brisken and Duss (2007).[46] Progesterone drives a string of events where luminal cells most likely present Wnt4 and RANKL signals to basal cells which consecutively react by upregulating their related receptors, transcriptional targets, and cell cycle markers, as per a recent finding by Joshi et al.[47] The strong control that estrogen and progesterone exert on breast cancer risk reinforces the advantage of endocrine therapies in breast cancer. Regulating their impact either by ovarian ablation or chemoprevention also appreciably decreases breast cancer incidence, while the risk of breast cancer is augmented with pregnancy in the short term. It is noteworthy to allude to some of the observations which clarify to some extent the molecular mechanism underlying these observations. The mouse MaSCs, despite being deficient in estrogen and progesterone receptors, have been shown to be extremely receptive to steroid hormone signaling. Oophorectomy resulted in marked reduction in MaSCs density and developmental potential in vivo, but mice treated with combined estrogen and progesterone had enhanced MaSC activity – just 3 weeks of treatment with aromatase inhibitor letrozole adequately lessened the MaSC pool. On the contrary, pregnancy induced a transitory 11-fold enhancement in MaSC numbers, possibly mediated through paracrine signaling from RANK ligand. The increased MaSC pool signifies a cellular basis for the transitory increase in breast cancer incidence that accompanies pregnancy. These observations support the feasibility of breast cancer chemoprevention in part through suppression of MaSC function.[48] On this note, it will be of interest to allude to an investigation by Luraguiz et al.[49] regarding the synergistic action of GSI and tamoxifen targeting both Notch and estrogen receptor positive tumor cells. The investigation showed that while GSI inhibitor of Notch pathway per se efficiently induced apoptosis in human breast cancer cell line ER-MDA- MB-231 cells, stem cell like cells were found to be very sensitive to GSI killing. The enhanced effect of combined GSI and tamoxifen signifies an effective strategy in treating breast cancer, targeting at both Notch signaling and estrogen receptor pathways in BCSCs.
Selective Targeting of BCSC
BCSC like somatic stem cells may oppose apoptosis by cytotoxic agents and radiation therapy, relative to the more differentiated cells that compose the mass of tumors. The CSCs show resistance to the more conservative therapies most probably due to the reactivation of diverse developmental signaling cascades
(epidermal growth factor-EFG/EGFR, stem cell factor (SCF)/KIT, SHH, Notch, and/or Wnt/-catenin) coupled with the increased DNA repair mechanisms and ABC transporter-mediated drug efflux in them. The resistance is probably compounded by changes in the local micromilieu of CSC. Recently, a core human embryonic stem cell (hESC) transcriptional profile was identified comprising OCT4, NANOG, STELLAR, CDF3, and NANOG protein in breast carcinoma. It was also discovered that hESCs express genes in common with primordial germ cells (PGCs), and of these, three genes (CDF3, STELLAR, and NANOG) are located on 12p. These observations imply that stem cell genes may participate directly in different types of carcinoma progression or are present as valuable markers of tumorigenesis.[50]
It is long been realized that relapsed or metastatic cancers are resistant to conventional chemotherapy. Therefore, new strategies are needed based on better understanding of signaling pathways which are obviously complex and intricate. Some of these have recently been investigated, namely PTEN/PI3 pathway located at chromosome 10, TP 53 for self-renewal, PTEN-AKT-Wnt pathway and Notch and SHH pathways in breast cancers.[24,25]
In this context, it merits mention that a study[51] on hyaluronan (HA)-induced interaction between CD44 (an HA receptor) and Nanog (an embryonic stem cell transcription factor) in human breast cancer tumor cells (MCF-7 cells) and human ovarian tumor cells (SK-OV-3.ipl cells) observed the expression of Nanog transcript in both tumor cell lines, as well as that HA binding to these tumor cells activates Nanog by stimulating Nanog protein link with CD44 and the expression of pluripotent stem cell regulators (Rex1 and sox2). Nanog leads to Stat-3 specific transcriptional activation and multidrug transporter MDR1 (P-glycoprotein) gene expression by forming a complex with the
“signal transducer and activator of transcription protein3” (Stat- 3) in the nucleus. It was also observed that Ha-CD44 interaction induces ankyrin (a cytoskeletal protein) binding to MDR1, leading to chemoresistance in these tumor cells. While Nanog overexpression prompts Stat-3 transcriptional activation, MRD1 overexpression and multidrug resistance downregulation of Nanog signaling or ankyrin function obstructs HA/CD44 mediated tumor cell behavior as well as increases chemosensitivity.
Thus, these observations imply a new alternative strategy of targeting HA?CD44 mediated Nanog–Stat-3 signaling pathways and ankyrin/cytoskeletal function to surmount chemotherapy resistance in some breast and ovarian tumor cells having stem cell marker properties during tumor development.[52-54]
It is also of interest at this junction to note that nucleostemin (NS), which is highly expressed in normal stem cells and tumors, is upregulated by estradiol in MCF7 breast cancer cells.
Higher levels of NS expression were noted in the basal cell type than in the luminal cell type in mouse mammary tumors and human breast cancer cells. Increased NS expression was noted throughout the progression of mammary tumors in MMTV- wnt1 and MMTV-PyMT transgenic mice. Clearly, NS-enriched mammary tumor cells, unlike NS-deficient mammary tumor cells,
151
had stronger tumorigenic activities and expressed elevated levels of K5, CD133, Oct4, telomerase reverse transcriptase, and C-X-C chemokine ligand12. The tumor initiating and molecular features of NS-enriched mammary tumor cells signify that NS may be a helpful therapeutic target.[55]
Elevated c-MYC, WNT Pathway in Mammary Epithelial Cells
It is noted that elevated c-MYC expression transforms the mammary epithelial cells as a result of which the cells show attributes of EMT and it promotes anchorage-independent growth change by c-MYC alone. In addition, c-MYC activates the Wnt signaling by suppressing transcription of the Wnt pathway inhibitors, DKK1 and SFRP1. It has also been shown that SFRP1 expression in vivo is appreciably reduced in MYC-induced mouse mammary tumors compared to those in wnt-1, Neu-1, and Ras- induced tumors. Contrary to previous observation that C-MYC is a transcriptional target of TCF/-catenin transactivation complex, He et al.[56] have shown that c-MYC activates the wnt pathway.
It has been proposed that in breast cancer, c-MYC and Wnt/TCF can operate in a positive regulatory loop. In normal mammary epithelial cells, Wnt/TCF activity is repressed by Wnt inhibitors such as DKK1 and SFRP1, and c-MYC gene expression is held in check. Oncogenic lesions that amplify the c-MYC locus increase c-MYC expression, which in turn represses DKK1 and SFRP1 and increases Wnt/TCF signaling. Active -catenin/TCF would further activate c-MYC gene expression, thus constituting a positive feedback loop as documented by Victoria H Cowling et al.[57]
MYC and NOTCH Pathway in Breast Cancer
Among the diverse activating mechanisms of Notch signaling in human breast cancer,[58,59] an autocrine mechanism of Notch pathway activation is suggested by the presence of coexpression of Jagged 1 ligand and Notch receptors in breast cancers, especially the triple negative (ER, PR, ErbB2 negative) subtype. [60] In addition, maintenance of pathway activity seems to be contributed by low levels of Numb, a negative regulator of Notch in ~50% of primary breast tumors.[61] Controlled ablation of MYC using the WAPCre transgene showed that MYC was vital for the development of NIC- derived mammary tumors. This role of MYC to Notch-induced tumorigenesis is of interest, especially compared to Wnt pathway- derived models. Moreover, MYC was shown to be a direct target of the Notch pathway, since a complex of NIC and Cbf1 was detected on the MYC promoter – the Cbf1 binding site on the human MYC levels and Nic in human breast tumors.[62,63] When the population of Notch effector Cbf in the mouse mammary stem cell (MaSC-enriched) was reduced, it augmented stem cell activity in vivo and development of abnormal end buds, thus attributing a role for endogenous Notch signaling in limiting MASC growth.
In contrast, Notch preferentially activated the ductal luminal epithelium in vivo and promoted exclusive differentiation of MaSC along the luminal linage. Constitutive Notch signaling in particular provoked the growth of luminal progenitor cells toward proliferation and neoplastic transformation. These findings imply that inappropriate Notch activation promotes the self-renewal and transformation of luminal progenitor cells.[46,58,64]
CONCLUSION
Existence of stem cells in most of the organ systems has been demonstrated and a molecular link between CSC and breast cancer has been established putatively. Challenges lying ahead for researchers encompass the role of stem cell niche, the nature of signals that the stem cells generate to influence their micromilieu, the factors that are involved in directing cells for appropriate emergence of differentiation, and the ultimate fate of these cells. With the increasing emergence of new promising tools and techniques to probe into the genomic sequencing and proteomic array within individual tumor cells, there is hope for seeing light at the end of the seemingly long tunnel on the evolution of cancer in the fullness of time from a benign cluster of aberrant cells to a malignant mass of hostile cells.[64] The successful eradication of breast cancer by therapy targeting cancer cells warrants further in- depth exploration and understanding of molecular mechanisms governing CSC self-renewal pathways, differentiation, and escape route of these cancer cells from conventional chemotherapy.
REFERENCES
1. Dantu G, Al-Hajj M, Abdallah WM, Clarke MF, Wicha MS. Stem cells in normal breast development and breast cancer. Cell Prolif 2003;36 (Suppl 1):59-72.
2. Kim C, Bryant J, horne Z. Trastuzumab sensitivity of breast cancer with co-amplification of HER2 and cMYC suggest pro-apoptotic function of dysregulated cMYC in vivo. Proceedings from the 28th annual San Antonio Breast Cancer Symposium. December 2005. Abstract #46.
3. Evan MJ, Kaufman MH. Establishment of culture of pluripotential cells from mouse embryos. Nature 1981;292:154-6.
4. Thomson J, Itskovitz-Eldor J, Shapiro S, Waknitz M, Swiergiel J, Marshall V, et al. Embryonic stem cell lines derived from human blastocyts. Science 1998;282:1145-7.
5. Reya T, Morrison S, Clarke M, Weissman I. Stem cells, cancer and cancer stem cells. Nature 2001;414:105-11.
6. Domen J, Cheshier SH, Weissman IL. The role of apaptosis in the regulation of hematopoitic stem cells: Overexpression of BCL-2 increases both their number and repopulation potential. J Exp Med 2000;191:253-64.
7. Lemischka IR, Morre KA. Stem cell: Interactive niches. Nature 2003;425:778-9.
8. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, et al. Osteoblastic cells regulate the haematopoietic stem cell niche.
Nature 2003;425:841-6.
9. Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, et al. Identification of the haematopoietic stem cell niche and control of the niche size.
Nature 2003;425:836-41.
10. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res 1961;25:585-621.
11. Hayflick L. The limited in vitro lifetime of human diploid cell strains.
Exp Cell 1965;37:614-36.
12. Olovnikov AM. Telomeres, telomerase and aging: Origin of the theory.
Exp Gerontol 1996;31:443-8.
13. Cairns J. Mutation selection and the natural history of cancer. Nature 1975;255:197-200.
14. Karpowicz P, Morshead C, Kam A, Jervis E, Ramunas J, Cheng V, et al.
Support for the immortal strand hypothesis: Neural stem cells partition DNA asymmetrically in vitro. J Cell Biol 2005;170:721-32.
15. Shinin V, Gayraud-Morel B, Gomes D, Tajbakhsh S. Asymmetric division
152
and cosegregation of template DNA strands in adult muscle satellite cells. Nature Cell Biology 2006;8:677-87.
16. Jang YY, Collector MI, Baylin SB, diehl AM, Sharkis SJ. Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol 2004;6:532-9.
17. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz- Gonzalez XR, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41-9.
18. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001;410:701-4.
19. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003;114:763-6.
20. Alison MR, Poulsom R, Forbes S, Wright NA. An introduction to stem cells. J Pathol 2002;197:419-23.
21. Zangani 2007-07-17. Available from: http://www.zangani.com/node/735.
Human stem cells may be produced without embryos “within months”.
22. Embryonic stem cells made without embryos. Reuters. 2007-11-21.
23. Rick Weiss (2007-12-07). Scientists cure Mice of sickle cell using stem cell technique: New approach is from skin, not embryos. Washington post. Pp; A02. Available from: http://www.washingtonpost.com/wpyn/
content/article/2007/12/06/AR200712062444.html.
24. Korinek V, Baker N, Moerer P, van Donselaar E, Huls G, Peters PJ, et al.
Depletion of epithelial stem cell compartment in small intestine of mice lacking Tcf-4. Nat Genet 1998;19:379-83.
25. He XC, Zhang J, Tong WG, Tawfik O, Ross J, Scoville DH, et al. BMP signaling inhibits intestinal stem cell self renewal through suppression of Wnt-beta-catenin signaling. Nat Genet 2004;36:1117-21.
26. Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell 2000;103:311-20.19.
27. Park IK, Morrison SJ, Clarke MF. Bmil, stem cells and senescence regulation. J Clin Invest 2004;113:175-9.
28. Tanos T, Brisken C. What signals operate in mammary niche? Breast Dis 2008;29:69-82.
29. Ganggemi R, Paleari L, Orengo AM, Cesario A, Chessa L, Ferrini S, et al. Cancer stem cells: A new paradigm for understanding tumour growth and progression and drug resistance. Curr Med Chem 2009;16:1688- 903.
30. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3:730-7.
31. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF.
Prospective identification of tumorigenic breast cancer cells. Proc Natl Aca Sci USA 2003;100:3983-8.
32. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al.
Identification of a cancer stem cell in human brain tumors. Cancer Res 2003;63:5821-8.
33. Tu LC, Folz G, Lin E, Hood L, Tian Q. Targeting stem cells- clinical implications for cancer therapy. Curr Stem Cell Ther 2009;4:147-53.
34. Korkaya H, Wicha MS. Selective targeting of cancer stem cells: A new concept in cancer therapeutics. BioDrugs 2007;21:299-310.
35. Christophe G, Min Hee Hur, Emmanuelle CJ. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem cell 2007;1:555-67 Available from:
http://www.ncbi.nlm.nih.gov.
36. Vaillant F, Asselin-Labat ML, Shackleton M, Forrest NC, Lindeman GJ, Visvader JE. The mammary progenitor marker CD61/3 integrin identifies cancer stem cells in mouse models of mammary tumorigenesis. Cancer Res 2008;68:7711-7.
37. Wicha MS, Liu S, Dontu G. Cancer stem cells: An old idea—A paradigm shift. Cancer Res 2006;66:1883-90.
38. Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin- Labat ML, et al. Generation of a functional mammary gland from a single stem cell. Nature 2006;439:84-8.
39. Farnie G, Clarke RB. Mammary stem cells and breast cancer- role of notch signaling. Stem Cell Rev 2007;3:169-75.
40. Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D, et al. Down regulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 2009;138:592-603.
41. Li Y, Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X, et al.
Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells.
Proc Natl Acad Sci USA 2003;100:15853-8.
42. Dimri GP, Martinez JL, Jacobs JJ, Keblusek P, Itahana K, Van Lohuizen M, et al. The Bmi1 oncogene induces telomerase activity and immortalizes human mammary epithelia cells. Cancer Res 2002;62:4736-45.
43. Jönsson G, Staaf J, Vallon-Christersson J, Ringnér M, Holm K, Hegardt C, et al. Genomic subtypes of breast cancer by array-comparative genomic hybridization display distinct molecular and clinical characteristics.
Breast Cancer Res 2010;12:R42.
44. Rizzo P, Miao H, D’Souza G, Osipo C, Song LL, Yun J, et al. Cross-talk between Notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches. Cancer Res 2008;68:5226-35.
45. Lim E, Wu D, Pal B, Bouras T, Asselin-Labat ML, Vaillant F, et al.
Transcription analysises of mouse and human mammary cell subpopulations reveal multiple conserved genes and pathways. Breast Cancer Res 2010;12:R21.
46. Brisken C, Duss S. Stem cells and the stem cell niche in the breast: An integrated hormonal and developmental perspective. Stem Cell Rev 2007;3:147-56.
47. Joshi PA, Jackson HW, Beristain AG, Di Grappa MA, Mote PA, Clarke CL, et al. Progesterone induces adult mammary stem cell expansion. Nature 2010;465:803-7.
48. Asselin-Labat ML, Vaillant F, Sherdan JM, Pal B, Wu D, Simpson ER, et al.
Control of mammary stem cell function by steroid hormone signaling.
Nature 2010;465:798-802.
49. Luragnuiz NS, Yong T, Yin H. Sun A. Targeting Notch signaling and estrogen receptor pathways in human breast cancer stem cells. J Clin Oncol 2008;26(May suppl):abstract 22066.
50. Ezeh UI, Turek PJ, Reijo RA, Clark AT. Human embryonic stem cell genes OCT4, NANOG, STELLAT and GDF3 are expressed in both seminoma and breast carcinoma. Cancer 2005;104:2255-65.
51. Bourguignon LY, Peyrollier K, Xia W, Gilad E. Hyaluronon-CD44- interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression and ankyrin-regulated multidrug efflux in breast and ovarian tumour cells. J Biol Chem 2008;283:17635-51.
52. Liu S, Dontu G, Wicha MS. Mammary stem cells, self renewal pathways and carcinogenesis. Breast Cancer Res 2005;7:86-95.
53. Charafe-Jauffret E, Monville F, Ginestier C, Dontu G, Birnbaum D, Wicha MS. Cancer stem cells in breast: Current opinion and future challenges. Pathobiology 2008;75:75-84.
54. Farnie G, Clarke RB. Breast stem cells and cancer. Ernst Schering Found Sym Proc 2006;5:141-53.
55. Lin T, Meng L, Li Y, Tsai RY. Tumour-initating function of nucleostemin- enriched mammary tumour cells. Cancer Res 2010;70:9444-52.
56. He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, et al.
Identification of c-MYC as a target of the APC pathway. Science 1998;281:1509-12.
57. Cowling VH, D’Cruz CM, Chodosh LA, Cole MD. C-MYC transforms human mammary epithelial cells through repression of the Wnt inhibitors DKK1 and SFRP1. Mol Cell Biol 2007;27:5135-46.
58. Bouras T, Pal B, Vaillant F, Harburg G, Asselin-Labat ML, Oakes SR, et al.
Notch signaling regulates mammary stem cell function and luminal cell-fate commitment. Cell Stem Cell 2008;3:429-41.
59. Philipp A, Schneider A, Väsrik I, Finke K, Xiong Y, Beach D, et al.
Repression of cyclin D1: Anovel function of MYC. Mol Cell Biol 1994;14:4032-43.
60. Sandgren EP, Scroeder JA, Qui TH, Palmiter RD, Brinster RL, Lee DC.
153 How to cite this article: Kumar DH, Kutty MK. Review of stem cell deregulation and breast cancer: An emerging hypothesis. Indian J Pathol Microbiol 2012;55:147-53.
Source of Support: Nil, Confl ict of Interest: None declared.
Inhibition of mammary gland involution is associated with transforming growth factor alpha but not c-myc-induced tumorigenesis in transgenic mice. Cancer Res 1995;55:3915-27.
61. Schoenenberger CA, Andes AC, Groner B, van der valk M, LeMeur M, Gerlinger P. Targeted c-myc gene expression in mammary glands of transgenic mice induces mammary tumours with constitutive milk protein gene transcription. EMBO J 1988;7:169-75.
62. Woodward WA, Chen MS, Behbod F, Rosen JM. On mammary stem cells. J Cell Sci 2005;118:3585-94.
63. Kakarala M, Wicha MS. Implication of cancer stem cell hypothesis for breast cancer prevention and therapy. J Clin Oncol 2008;26:2813-20.
64. Barabe F, Kennedy JA, Hope KJ, Dick JE. Modelling the initiation and progression of human acute leukemia in mice. Science 2007;316:600-4.
“QUICK RESPONSE CODE” LINK FOR FULL TEXT ARTICLES
The journal issue has a unique new feature for reaching to the journal’s website without typing a single le er. Each ar cle on its fi rst page has a “Quick Response Code”. Using any mobile or other hand-held device with camera and GPRS/other internet source, one can reach to the full text of that par cular ar cle on the journal’s website. Start a QR-code reading so ware (see list of free applica ons from h p:// nyurl.com/yzlh2tc) and point the camera to the QR-code printed in the journal. It will automa cally take you to the HTML full text of that ar cle. One can also use a desktop or laptop with web camera for similar func onality. See h p:// nyurl.com/2bw7fn3 or h p:// nyurl.com/3ysr3me for the free applica ons.
Announcement
