Identifying thyroid stem/progenitor cells: advances and limitations

Continuing advances in stem cell science have prompted researchers to envisage the potential application of stem cells for the management of several debilitating disorders, thus raising the expectations of transplant clinicians. In particular, in order to find a source of adult stem cells alternative to embryonic stem cells (ESCs) for the exploration of novel strategies in regenerative medicine, researchers have attempted to identify and characterise adult stem/progenitor cells resident in compact organs, since these populations appear to be responsible for physiological tissue renewal and regeneration after injury. In particular, recent studies have also reported evidence for the existence of adult stem/progenitor cell populations in both mouse and human thyroids. Here, I provide a review of published findings about ESC lines capable of generating thyroid follicular cells, thyroid somatic stem cells and cancer stem cells within the thyroid. The three subjects are analysed by also considering the criticism recently raised against their existence and potential utility. I comment specifically on the significance of resident thyroid stem cells in the developmental biology of the gland and their putative role in the pathogenesis of thyroid disorders and on the protocols employed for their identification. I finally provide my opinion on whether from basic science results obtained to date it is possible to extrapolate any convincing basic for future treatment of thyroid disorders.     

Endometrial regeneration and endometrial stem/progenitor cells

The functional layer of the human endometrium is a highly regenerative tissue undergoing monthly cycles of growth, differentiation and shedding during a woman??s reproductive years. Fluctuating levels of circulating estrogen and progesterone orchestrate this dramatic remodeling of human endometrium. The thin inactive endometrium of postmenopausal women which resembles the permanent basal layer of cycling endometrium retains the capacity to respond to exogenous sex steroid hormones to regenerate into a thick functional endometrium capable of supporting pregnancy. Endometrial regeneration also follows parturition and endometrial resection. In non menstruating rodents, endometrial epithelium undergoes rounds of proliferation and apoptosis during estrus cycles. The recent identification of adult stem cells in both human and mouse endometrium suggests that epithelial progenitor cells and the mesenchymal stem/stromal cells have key roles in the cyclical regeneration of endometrial epithelium and stroma. This review will summarize the evidence for endometrial stem/progenitor cells, examine their role in mouse models of endometrial epithelial repair and estrogen-induced endometrial regeneration, and also describe the generation of endometrial-like epithelium from human embryonic stem cells. With markers now available for identifying endometrial mesenchymal stem/stromal cells, their possible role in gynecological diseases associated with abnormal endometrial proliferation and their potential application in cell-based therapies to regenerate reproductive and other tissues will be discussed.     

Thrombopoietin stimulation of hematopoietic stem/progenitor cells

The recent cloning of the thrombopoietin gene, and the production of recombinant protein, have allowed studies on both its biological actions and clinical utility. Thrombopoietin not only affects the cells of the megakaryocytic lineage, but has a diverse set of cellular targets. In particular, it stimulates the ex vivo expansion of hematopoietic stem/progenitor cells suggesting that it may play a role in transplantation studies. Pre-clinical but limited clinical studies indicate that under defined conditions, thrombopoietin may accelerate white blood cell count and platelet recoveries following myelosuppression or radiotherapy.     

Wnt-mediated self-renewal of neural stem/progenitor cells

In this work we have uncovered a role for Wnt signaling as an important regulator of stem cell self-renewal in the developing brain. We identified Wnt-responsive cells in the subventricular zone of the developing E14.5 mouse brain. Responding cell populations were enriched for self-renewing stem cells in primary culture, suggesting that Wnt signaling is a hallmark of self-renewing activity in vivo. We also tested whether Wnt signals directly influence neural stem cells. Using inhibitors of the Wnt pathway, we found that Wnt signaling is required for the efficient cloning and expansion of single-cell derived populations that are able to generate new stem cells as well as neurons, astrocytes, and oligodendrocytes. The addition of exogenous Wnt3a protein enhances clonal outgrowth, demonstrating not only a critical role for the Wnt pathway for the regulation of neurogenesis but also its use for the expansion of neural stem cells in cell culture and in tissue engineering.     

Hepatic stem cells： existence and origin

Stem cells are not only units of biological organization,responsible for the development and the regeneration of tissue and organ systems, but also are units in evolution by natural selection. It is accepted that there is stem cell potential in the liver. Like most organs in a healthy adult,the liver maintains a perfect balance between cell gain and loss. It has three levels of cells that can respond to loss of hepatocytes: (1) Mature hepatocytes, which proliferate after normal liver tissue renewal, less severe liver damage, etc;they are numerous, unipotent, “committed“ and respond rapidly to liver injury. (2) Oval cells, which are activated to proliferate when the liver damage is extensive and chronic,or if proliferation of hepatocytes is inhibited; they lie within or immediately adjacent to the canal of Hering (Coil); they are less numerous, bipotent and respond by longer, but still limited proliferation. (3) Exogenous liver stem cells, which may derive from circulating hematopoietic stem cells (HSCs) or bone marrow stem cells; they respond to allyl alcohol injury or hepatocarcinogenesis; they are multipotent, rare,but have a very long proliferation potential. They make a more significant contribution to regeneration, and even completely restore normal function in a murine model of hereditary tyrosinaemia. How these three stem cell populations integrate to achieve a homeostatic balance remains enigmatic. This review focuses on the location,activation, markers of the three candidates of liver stem cell, and the most importantly, therapeutic potential of hepatic stem cells.     

Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals

The limited vessel-forming capacity of infused endothelial progenitor cells (EPCs) into patients with cardiovascular dysfunction may be related to a misunderstanding of the biologic potential of the cells. EPCs are generally identified by cell surface antigen expression or counting in a commercially available kit that identifies "endothelial cell colony-forming units" (CFU-ECs). However, the origin, proliferative potential, and differentiation capacity of CFU-ECs is controversial. In contrast, other EPCs with blood vessel-forming ability, termed endothelial colony-forming cells (ECFCs), have been isolated from human peripheral blood. We compared the function of CFU-ECs and ECFCs and determined that CFU-ECs are derived from the hematopoietic system using progenitor assays, and analysis of donor cells from polycythemia vera patients harboring a Janus kinase 2 V617F mutation in hematopoietic stem cell clones. Further, CFU-ECs possess myeloid progenitor cell activity, differentiate into phagocytic macrophages, and fail to form perfused vessels in vivo. In contrast, ECFCs are clonally distinct from CFU-ECs, display robust proliferative potential, and form perfused vessels in vivo. Thus, these studies establish that CFU-ECs are not EPCs and the role of these cells in angiogenesis must be re-examined prior to further clinical trials, whereas ECFCs may serve as a potential therapy for vascular regeneration.     

过氧化损伤及抗氧化能力时间动态变化与造血干/祖细胞衰老的相关性

目的 探讨增龄过程中小鼠Sca-1+造血干/祖细胞(Sca-1+ HSC/HPC)过氧化损伤及抗氧化能力的动态变化与其衰老的关系.方法 C57BL/6J雄性小鼠分为幼年组(3～4周龄),青年组(2月龄),中年组(6月龄),中老年组(12月龄),老年组(18月龄).提取各组小鼠骨髓单个核细胞,免疫磁性吸附细胞分选法(MACS)分离纯化Sca-1+细胞群,WST法检测细胞超氧化物歧化酶(SOD)含量,TNB显色法检测细胞总谷胱甘肽(GSSG+ GSH)含量,WST-1法检测超氧化物含量,硫代巴比妥酸法检测丙二醛(MDA)含量,衰老相关β-半乳糖苷酶(SA-β-gal)染色观察各年龄组阳性细胞百分比,造血祖细胞混合集落培养比较各年龄组Sca-i+细胞形成集落能力.结果 总SOD活力值、GSSG+ GSH含量、超氧化物含量吸光度、MDA含量、SA-β-Gal阳性细胞百分比及混合集落形成率分别在幼年组为(27.51±1.11)U/g、(28.78±0.77)μmol/L、(0.114±0.005)、(2.06±0.54)nmol/mg、(2.26±0.65)％、(8.79±0.56);青年组为(38.23±3.50) U/g、(31.48±2.03) μmol/L、(0.109±0.005)、(0.81±0.35) nmol/mg、(9.08±2.74)％、(9.48±0.74);中年组为(28.85±0.65) U/g、(47.62±4.93) μmol/L、(0.133±0.002)、(2.69±0.62) nmol/mg、(11.58±0.89)％、(5.14±0.89);中老年组(12.67±0.89) U/g、(25.63±1.23) μmol/L、(0.151±0.009)、(11.44±1.19) nmol/mg、(35.34±2.50)％、(1.56±0.23);老年组为(17.52±1.27)U/g、(39.10±2.19) μmol/L、(0.141±0.005)、(7.06±0.95) nmol/mg、(15.76±1.23]％、(0.98±0.50).结论 随年龄增加Sca-1+ HSC/HPC的SA-β-Gal阳性细胞百分比逐渐增高,混合集落形成能力下降,SOD活性、GSSG+ GSH含量逐步降低,而超氧化物、MDA含量逐渐增加,提示在增龄过程Sca-1+ HSC/HPC过氧化损伤,抗氧化能力逐渐降低是造血干细胞衰老的可能机制之一.     

Role of microRNAs in stem/progenitor cells and cardiovascular repair

MicroRNAs (miRNAs), small non-coding RNAs, play a critical role in differentiation and self-renewal of pluripotent stem cells, as well as in differentiation of cardiovascular lineage cells. Several miRNAs have been demonstrated to repress stemness factors such as Oct4, Nanog, Sox2 and Klf4 in embryonic stem cells, thereby promoting embryonic stem cell differentiation. Furthermore, targeting of different miRNAs promotes reprogramming towards induced pluripotent stem cells. MicroRNAs are critical for vascular smooth muscle cell differentiation and phenotype regulation, and miR-143 and miR-145 play a particularly important role in this respect. Notably, these miRNAs are down-regulated in several cardiovascular disease states, such as in atherosclerotic lesions and vascular neointima formation. MicroRNAs are critical regulators of endothelial cell differentiation and ischaemia-induced neovascularization. miR-126 is important for vascular integrity, endothelial cell proliferation and neovascularization. miR-1 and miR-133 are highly expressed in cardiomyocytes and their precursors and regulate cardiomyogenesis. In addition, miR-499 promotes differentiation of cardiomyocyte progenitor cells. Notably, miRNA expression is altered in cardiovascular disease states, and recent studies suggest that dysregulated miRNAs may limit cardiovascular repair responses. Dysregulation of miRNAs may lead to an altered function and differentiation of cardiovascular progenitor cells, which is also likely to represent a limitation of autologous cell-based treatment approaches in these patients. These findings suggest that targeting of specific miRNAs may represent an interesting novel opportunity to impact on endogenous cardiovascular repair responses, including effects on stem/progenitor cell differentiation and functions. This approach may also serve to optimize cell-based treatment approaches in patients with cardiovascular disease.     

Identification and characterization of tumorigenic liver cancer stem/progenitor cells

BACKGROUND & AIMS: Recent efforts in stem cell biology suggest that tumors are organized in a hierarchy of heterogeneous cell populations and that the capability to maintain tumor formation/growth specifically resides in a small population of cells called cancer stem cells (CSCs). The aim of this study is to identify, isolate, and characterize the CSC population that drives and maintains hepatocellular carcinoma (HCC) growth and metastasis. METHODS: Normal stem cells involved in liver regeneration were identified using a severe partial hepatectomy model. Purified HCC cells, with or without expression of the identified normal stem cell phenotype, were evaluated, based on their tumorigenic potential and exhibition of defined stem/progenitor cell-like properties, to determine whether liver CSCs can be or partly be identified by this surface marker. RESULTS: We report the identification and isolation of a population of CSCs expressing a CD133 surface phenotype from human liver cell lines. CD133(+) cells possess a greater colony-forming efficiency, higher proliferative output, and greater ability to form tumor in vivo. These cells are endowed with characteristics similar to those of progenitor cells including the expression of "stemness" genes, the ability to self-renew, and the ability to differentiate into nonhepatocyte-like lineages. Furthermore, CD133 is found to represent only a minority of the tumor cell population in human HCC specimens. CONCLUSIONS: We report the identification of a CSC population in HCC characterized by their CD133 phenotype. The identification of tumorigenic liver CSCs could provide new insight into the HCC tumorigenic process and possibly bear great therapeutic implications.     

Pancreatic stem/progenitor cells for the treatment of diabetes

Patients with type 1 diabetes, and most patients with type 2 diabetes, have associated hyperglycemia due to the absence or reduction of insulin production by pancreatic β-cells. Surgical resection of the pancreas may also cause insulin-dependent diabetes depending on the size of the remaining pancreas. Insulin therapy has greatly improved the quality of life of diabetic patients, but this method is inaccurate and requires lifelong treatment that only mitigates the symptoms. The successes achieved over the last few decades by the transplantation of whole pancreas and isolated islets suggest that diabetes can be cured by the replenishment of deficient β-cells. These observations are proof-of-principle and have intensified interest in treating diabetes by cell transplantation, and by the use of stem cells. Pancreatic stem/progenitor cells could be one of the sources for the treatment of diabetes. Islet neogenesis, the budding of new islets from pancreatic stem/progenitor cells located in or near pancreatic ducts, has long been assumed to be an active process in the postnatal pancreas. Several in vitro studies have shown that insulin-producing cells can be generated from adult pancreatic ductal tissues. Acinar cells may also be a potential source for differentiation into insulin-producing cells. This review describes recent progress on pancreatic stem/progenitor cell research for the treatment of diabetes.     

内源性心脏干/祖细胞活化的研究进展

随着现代生活方式的改变和老龄化的问题,心血管疾病已成为威胁人类健康的第一杀手。然而当前医疗诊治技术仍难以彻底改善心肌梗死后缺血性心肌病及心力衰竭患者的预后。干细胞的出现为心肌再生带来了新的希望。与其他成体干细胞相比,内源性心脏干细胞(CSCs)具有分化成心肌细胞和血管内皮细胞的潜能,可对受损心肌起到明显的修复作用。研究发现,心肌梗死后内源性CSCs的激活与多种因素有关。最近几年,内源性CSCs活化介导的心肌修复引起了研究人员极大的兴趣。本文将对CSCs激活所涉及的主要途径进行论述,以深化对内源性CSCs功能的理解。     

The canonical Wnt pathway shapes niches supportive of hematopoietic stem/progenitor cells

Considerable information has accumulated about components of BM that regulate the survival, self-renewal, and differentiation of hematopoietic cells. In the present study, we investigated Wnt signaling and assessed its influence on human and murine hematopoiesis. Hematopoietic stem/progenitor cells (HSPCs) were placed on Wnt3a-transduced OP9 stromal cells. The proliferation and production of B cells, natural killer cells, and plasmacytoid dendritic cells were blocked. In addition, some HSPC characteristics were maintained or re-acquired along with different lineage generation potentials. These responses did not result from direct effects of Wnt3a on HSPCs, but also required alterations in the OP9 cells. Microarray, PCR, and flow cytometric experiments revealed that OP9 cells acquired osteoblastic characteristics while down-regulating some features associated with mesenchymal stem cells, including the expression of angiopoietin 1, the c-Kit ligand, and VCAM-1. In contrast, the production of decorin, tenascins, and fibromodulin markedly increased. We found that at least 1 of these extracellular matrix components, decorin, is a regulator of hematopoiesis: upon addition of this proteoglycan to OP9 cocultures, decorin caused changes similar to those caused by Wnt3a. Furthermore, hematopoietic stem cell numbers in the BM and spleen were elevated in decorin-knockout mice. These findings define one mechanism through which canonical Wnt signaling could shape niches supportive of hematopoiesis.     

Ex vivo culture of Fancc-/- stem/progenitor cells predisposes cells to undergo apoptosis, and surviving stem/progenitor cells display cytogenetic abnormalities and an increased risk of malignancy

Current strategies for genetic therapy using Moloney retroviruses require ex vivo manipulation of hematopoietic cells to facilitate stable integration of the transgene. While many studies have evaluated the impact of ex vivo culture on normal murine and human stem/progenitor cells, the cellular consequences of ex vivo manipulation of stem cells with intrinsic defects in genome stability are incompletely understood. Here we show that ex vivo culture of Fancc(-/-) bone marrow cells results in a time-dependent increase in apoptosis of primitive Fancc(-/-) progenitor cells in conditions that promote the proliferation of wild-type stem/progenitor cells. Further, recipients reconstituted with the surviving Fancc(-/-) cells have a high incidence of cytogenetic abnormalities and myeloid malignancies that are associated with an acquired resistance to tumor necrosis factor alpha (TNF-alpha). Collectively, these data indicate that the intrinsic defects in the genomic stability of Fancc(-/-) stem/progenitor cells provide a selective pressure for cells that are resistant to apoptosis and have a propensity for the evolution to clonal hematopoiesis and malignancy. These studies could have implications for the design of genetic therapies for treatment of Fanconi anemia and potentially other genetic diseases with intrinsic defects in genome stability.     

The iron chelator deferasirox affects redox signalling in haematopoietic stem/progenitor cells

The iron chelator deferasirox (DFX) prevents complications related to transfusional iron overload in several haematological disorders characterized by marrow failure. It is also able to induce haematological responses in a percentage of treated patients, particularly in those affected by myelodysplastic syndromes. The underlying mechanisms responsible for this feature, however, are still poorly understood. In this study, we investigated the effect of DFX‐treatment in human haematopoietic/progenitor stem cells, focussing on its impact on the redox balance, which proved to control the interplay between stemness maintenance, self‐renewal and differentiation priming. Here we show, for the first time, that DFX treatment induces a significant diphenyleneiodonium‐sensitive reactive oxygen species (ROS) production that leads to the activation of POU5F1 (OCT4), SOX2 and SOX17 gene expression, relevant in reprogramming processes, and the reduction of the haematopoietic regulatory proteins CTNNB1 (β‐Catenin) and BMI1. These DFX‐mediated events were accompanied by decreased CD34 expression, increased mitochondrial mass and up‐regulation of the erythropoietic marker CD71 (TFRC) and were compound‐specific, dissimilar to deferoxamine. Our findings would suggest a novel mechanism by which DFX, probably independently on its iron‐chelating property but through ROS signalling activation, may influence key factors involved in self‐renewal/differentiation of haematopoietic stem cells.     

Cancer origin in committed versus stem cells: hypothetical antineoplastic mechanism/s associated with stem cells

It has been assumed for a long time that cancer originates in stem cells, the so-called stem cell theory of cancer origin. However, the origin of cancer in committed cells is becoming increasingly recognised. The author discusses accumulated data suggesting the preferential origin of cancer in committed cells. From histopathological, clinical and biological features, two broad tumour categories are here delineated according to the presumed cell stage of malignant transformation: common adult cancers and childhood/undifferentiated tumours corresponding to late and early stage origin, respectively. Higher cancer incidence in committed than stem cells, as well as other observations presented is consistent with the existence of an anti-cancer protective mechanism/s specific to stem cells postulated in a previous paper. Furthermore, two important carcinogenic pathways, the telomere attrition pathway and INK4a pathway, are expected to spare stem cells from direct cancer transformation. It is suggested that these two pathways are differentially involved in the two broad tumour categories delineated.     

Hormone and growth factor signaling in endometrial renewal: Role of stem/progenitor cells

The human endometrium is a dynamic remodeling tissue undergoing more than 400 cycles of regeneration, differentiation and shedding during a woman's reproductive years. The co-ordinated and sequential actions of estrogen and progesterone direct these major remodeling events preparing a receptive endometrium for blastocyst implantation on a monthly basis. Adult stem/progenitor cells are likely responsible for endometrial regeneration. Functional approaches have been used to identify candidate endometrial stem/progenitor cells, as there are no specific stem cell markers. Rare populations of human endometrial epithelial and stromal colony-forming cells/units (CFU) and side population (SP) cells have been identified. Several growth factors are required for CFU activity: epidermal growth factor (EGF), transforming growth factor α (TGFα) and platelet-derived growth factor BB (PDGF-BB) for both epithelial and stromal CFU, and basic fibroblast growth factor (bFGF) for stromal, but not epithelial CFU. A sub-population of human endometrial stromal cells with mesenchymal stem cell properties of CFU activity and multilineage (fat, muscle, cartilage and bone) differentiation have been isolated by their co-expression of CD146 and PDGF-receptor β. Candidate epithelial and stromal stem/progenitor cells have been identified in mouse endometrium as rare label retaining cells (LRCs) in the luminal epithelium and as perivascular cells at the endometrial–myometrial junction, respectively. While epithelial and most stromal LRC do not express estrogen receptor α (Esr1), they rapidly proliferate on estrogen stimulation, most likely mediated by neighbouring Esr1-expressing niche cells. It is likely that these newly identified endometrial stem/progenitor cells may play key roles in the development of gynecological diseases associated with abnormal endometrial proliferation such as endometriosis and endometrial cancer.     

Hormone and growth factor signaling in endometrial renewal: role of stem/progenitor cells

The human endometrium is a dynamic remodeling tissue undergoing more than 400 cycles of regeneration, differentiation and shedding during a woman's reproductive years. The co-ordinated and sequential actions of estrogen and progesterone direct these major remodeling events preparing a receptive endometrium for blastocyst implantation on a monthly basis. Adult stem/progenitor cells are likely responsible for endometrial regeneration. Functional approaches have been used to identify candidate endometrial stem/progenitor cells, as there are no specific stem cell markers. Rare populations of human endometrial epithelial and stromal colony-forming cells/units (CFU) and side population (SP) cells have been identified. Several growth factors are required for CFU activity: epidermal growth factor (EGF), transforming growth factor alpha (TGFalpha) and platelet-derived growth factor BB (PDGF-BB) for both epithelial and stromal CFU, and basic fibroblast growth factor (bFGF) for stromal, but not epithelial CFU. A sub-population of human endometrial stromal cells with mesenchymal stem cell properties of CFU activity and multilineage (fat, muscle, cartilage and bone) differentiation have been isolated by their co-expression of CD146 and PDGF-receptor beta. Candidate epithelial and stromal stem/progenitor cells have been identified in mouse endometrium as rare label retaining cells (LRCs) in the luminal epithelium and as perivascular cells at the endometrial-myometrial junction, respectively. While epithelial and most stromal LRC do not express estrogen receptor alpha (Esr1), they rapidly proliferate on estrogen stimulation, most likely mediated by neighbouring Esr1-expressing niche cells. It is likely that these newly identified endometrial stem/progenitor cells may play key roles in the development of gynecological diseases associated with abnormal endometrial proliferation such as endometriosis and endometrial cancer.     

Adrenocortical stem and progenitor cells: implications for adrenocortical carcinoma

The continuous centripetal repopulation of the adrenal cortex is consistent with a population of cells endowed with the stem/progenitor cell properties of self-renewal and pluripotency. The adrenocortical capsule and underlying undifferentiated cortical cells are emerging as critical components of the stem/progenitor cell niche. Recent genetic analysis has identified various signaling pathways including Sonic Hedgehog (Shh) and Wnt as crucial mediators of adrenocortical lineage and organ homeostasis. Shh expression is restricted to the peripheral cortical cells that express a paucity of steroidogenic genes but give rise to the underlying differentiated cells of the cortex. Wnt/β-catenin signaling maintains the undifferentiated state and adrenal fate of adrenocortical stem/progenitor cells, in part through induction of its target genes Dax1 and inhibin-α, respectively. The pathogenesis of ACC, a rare yet highly aggressive cancer with an extremely poor prognosis, is slowly emerging from studies of the stem/progenitor cells of the adrenal cortex coupled with the genetics of familial syndromes in which ACC occurs. The frequent observation of constitutive activation of Wnt signaling due to loss-of-function mutations in the tumor suppressor gene APC or gain-of-function mutation in β-catenin in both adenomas and carcinomas, suggests perhaps that the Wnt pathway serves an early or initiating insult in the oncogenic process. Loss of p53 might be predicted to cooperate with additional genetic insults such as IGF2 as both are the most common genetic abnormalities in malignant versus benign adrenocortical neoplasms. It is unclear whether other factors such as Pod1 and Pref1, which are implicated in stem/progenitor cell biology in the adrenal and/or other organs, are also implicated in the etiology of adrenocortical carcinoma. The rarity and heterogeneous presentation of ACC makes it difficult to identify the cellular origin and the molecular progression to cancer. A more complete understanding of adrenocortical stem/progenitor cell biology will invariably aid in characterization of the molecular details of ACC tumorigenesis and may offer new options for therapeutic intervention.     

Breast cancer, stem/progenitor cells and the estrogen receptor.

Recently, substantial progress has been made in the identification and characterization of stem and progenitor cells in the mouse and human mammary gland. Furthermore, there is accumulating evidence that these cells might be targets for transformation during mammary carcinogenesis. On the basis of this stem cell concept, we propose a model in which the transformation of different subsets of stem and progenitor cells results in the diversity of breast cancer phenotypes, including expression of the estrogen receptor in breast cancers subtypes. This model has important implications for understanding mammary carcinogenesis. Furthermore, the concept of breast cancer as a disease of mammary stem and progenitor cells has profound implications for the development of new strategies for breast cancer prevention and therapy.