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  Table of Contents    
REVIEW ARTICLE  
Year : 2012  |  Volume : 55  |  Issue : 2  |  Page : 147-153
Review of stem cell deregulation and breast cancer: An emerging hypothesis


1 Pathology, Monash University Sunway campus, Johor Bahru, Malaysia
2 Pathology, Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, Kuala Lumpur, Malaysia

Click here for correspondence address and email

Date of Web Publication3-Jul-2012
 

   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, significant stress is laid on targeting signaling molecules and their micromilieu in breast cancer therapy.

Keywords: Cancer, molecular pathways, progenitor cell, stem cell, targeted therapy

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

How to cite this URL:
Kumar DH, Kutty MK. Review of stem cell deregulation and breast cancer: An emerging hypothesis. Indian J Pathol Microbiol [serial online] 2012 [cited 2020 Feb 25];55:147-53. Available from: http://www.ijpmonline.org/text.asp?2012/55/2/147/97842



   Introduction Top


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],[5],[6],[7],[8],[9]

In contrast, the adult cells have somewhat limited plasticity, self-renewal, and self-maintenance (Hayflick effect) related to telomere shortening. [10],[11],[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],[13],[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 Top


It is still not clearly known how stem cell activities are controlled by different 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],[25],[26],[27],[28],[29],[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],[32],[33] which may help release of chemotherapeutics from the cells.


   Breast Cancer Stem Cell Top


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],[33],[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/β3 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 tumor cells with secondary mutation, loss of PTEN, indicative of their origin from a common progenitor. Mammary tumors in transgenic mice expressing β-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/p21 waf 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 Identification

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],[29],[30],[31],[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.
Figure 1: Proposed molecular origin of breast cancer based on global DNA copy number aberration and gene expression profile

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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 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/β-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],[53],[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, 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/β-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 β-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 N IC -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 N IC and Cbf1 was detected on the MYC promoter - the Cbf1 binding site on the human MYC levels and N ic 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 Top


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.

 
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Correspondence Address:
Methil Kannan Kutty
Pathology, Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, Kuala Lumpur
Malaysia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.97842

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