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Role of Notch Signaling in Cell-Fate Determination of Human Mammary

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Role of Notch Signaling in Cell-Fate Determination of Human Mammary Available online http://breast-cancer-research.com/content/6/6/R605 ResearchVol 6 No 6 article Open Access Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells Gabriela Dontu, Kyle W Jackson, Erin McNicholas, Mari J Kawamura, Wissam M Abdallah and Max S Wicha Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA Corresponding author: Gabriela Dontu, [email protected] Received: 6 Apr 2004 Revisions requested: 10 May 2004 Revisions received: 28 Jun 2004 Accepted: 15 Jul 2004 Published: 16 Aug 2004 Breast Cancer Res 2004, 6:R605-R615 (DOI 10.1186/bcr920)http://breast-cancer-research.com/content/6/6/R605 © 2004 Dontu et al.; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. Abstract Introduction Notch signaling has been implicated in the renewal and on early progenitor cells to promote their regulation of cell-fate decisions such as self-renewal of adult proliferation, as demonstrated by a 10-fold increase in stem cells and differentiation of progenitor cells along a secondary mammosphere formation upon addition of a Notch- particular lineage. Moreover, depending on the cellular and activating DSL peptide. In addition to acting on stem cells, developmental context, the Notch pathway acts as a regulator of Notch signaling is also able to act on multipotent progenitor cell survival and cell proliferation. Abnormal expression of Notch cells, facilitating myoepithelial lineage-specific commitment and receptors has been found in different types of epithelial proliferation. Stimulation of this pathway also promotes metaplastic lesions and neoplastic lesions, suggesting that branching morphogenesis in three-dimensional Matrigel Notch may act as a proto-oncogene. The vertebrate Notch1 and cultures. These effects are completely inhibited by a Notch4 Notch4 homologs are involved in normal development of the blocking antibody or a gamma secretase inhibitor that blocks mammary gland, and mutated forms of these genes are Notch processing. In contrast to the effects of Notch signaling associated with development of mouse mammary tumors. on mammary stem/progenitor cells, modulation of this pathway has no discernable effect on fully committed, differentiated, Methods In order to determine the role of Notch signaling in mammary epithelial cells. mammary cell-fate determination, we have utilized a newly described in vitro system in which mammary stem/progenitor cells can be cultured in suspension as nonadherent Conclusion These studies suggest that Notch signaling plays a 'mammospheres'. Notch signaling was activated using critical role in normal human mammary development by acting exogenous ligands, or was inhibited using previously on both stem cells and progenitor cells, affecting self-renewal characterized Notch signaling antagonists. and lineage-specific differentiation. Based on these findings we propose that abnormal Notch signaling may contribute to Results Utilizing this system, we demonstrate that Notch mammary carcinogenesis by deregulating the self-renewal of signaling can act on mammary stem cells to promote self- normal mammary stem cells. Keywords: mammary gland development, mammary progenitor cells, mammary stem cells, Notch Introduction of identified specific cell surface markers. Furthermore, Stem cells in adult tissues are characterized by their ability investigation of the mechanisms underlying cell-fate deci- to undergo self-renewal and multilineage differentiation [1]. sions in mammary stem/progenitor cells has been limited The elucidation of pathways that govern stem cell functions by the lack of suitable in vitro culture systems, which main- is essential for understanding normal development and org- tain these cells in an undifferentiated state [3]. anogenesis. Moreover, there is increasing evidence that defects in these pathways play an important role in carcino- We have recently described an in vitro culture system that genesis [2]. The isolation of stem cells from the mammary allows for the propagation of primary human mammary epi- gland in humans and rodents has been hindered by the lack thelial stem cells and progenitor cells in an undifferentiated ADAM = a disintegrin and metalloproteases; FACS = fluoresence-activated cell sorting; FBS = fetal bovine serum; FITC = fluorescein isothiocyanate; GSI = gamma secretase inhibitor; HBSS = Hanks Balanced Salt Solution; RT-PCR = reverse transcriptase-polymerase chain reaction. R605 Breast Cancer Research Vol 6 No 6 Dontu et al. state, based on their ability to proliferate in suspension as Mammospheres were collected by gentle centrifugation spherical structures, which we have termed 'nonadherent (800 rpm) after 7–10 days, and were dissociated enzymat- mammospheres' [4]. As has previously been described for ically (10 min in 0.05% trypsin, 0.53 mM EDTA-4Na; Invit- neuronal stem cells and progenitor cells cultured as neuro- rogen) and mechanically, using a fire-polished Pasteur spheres [5], we have demonstrated that mammospheres pipette. The cells obtained from dissociation were sieved are composed of stem cells and progenitor cells capable of through a 40 µm sieve and analyzed microscopically for sin- self-renewal and multilineage differentiation [4]. We have gle cellularity. Cells plated at low densities (1000 cells/ml) utilized this system to investigate the role of Notch signal- were grown in conditioned medium from high-density pri- ing in mammary cell-fate determination. mary cultures in suspension. In other systems, Notch signaling has been shown to play Differentiating culture conditions an important role in cell-fate determination, as well as in cell Single cell suspensions were plated on collagen-coated survival and proliferation [6,7]. The Notch proteins, repre- plates at a density of 2000 viable cells/10 cm diameter sented by four homologs in mammals (Notch1–Notch4), dish. Cells were grown in Ham's F-12 medium (BioWhit- interact with a number of surface-bound or secreted lig- taker) with 5% fetal bovine serum (FBS), 5 µg/ml insulin, 1 ands (Delta-like 1, Delta-like 3, Delta-like 4, Jagged 1 and µg/ml hydrocortisone, 10 µg/ml cholera toxin (Sigma, St Jagged 2) [8-10]. These interactions are modulated by Louis, MO, USA), 10 ng/ml epidermal growth factor (BD modifier proteins from the Fringe family (Lunatic, Manic, Biosciences) and 1 × Pen/Strep/Fungizone Mix (BioWhit- and Radical Fringe) [11]. Upon ligand binding, Notch taker). Three-dimensional cultures in Matrigel were estab- receptors are activated by serial cleavage events involving lished as previously described [18]. members of the ADAM protease family, as well as an intramembranous cleavage regulated by gamma secretase Immunostaining (presinilin). This intramembranous cleavage is followed by To assess the lineage composition of the colonies, cells translocation of the intracellular domain on Notch to the were fixed on plates for 20 min in methanol, at -20°C, and nucleus, where it acts on downstream targets [11]. The ver- were then stained using Peroxidase Histostain-Plus and tebrate Notch4 gene has been shown to be involved in nor- Alkaline-phosphatase Histostain-Plus kits (Zymed, South mal mammary development [12]. In vitro, overexpression of San Francisco, CA, USA), according to the manufacturer's a constitutively active form of Notch4 inhibits differentiation protocol. The ductal–alveolar structures were fixed in of normal breast epithelial cells [13]. In vivo, transgenic Matrigel in 4% neutral formalin, and treated with 1 mg/ml mice expressing a constitutively active form of Notch4 fail proteinase K for 10–15 min at room temperature, prior to to develop normal mammary glands and subsequently staining. For immunostaining in Matrigel, all antibody incu- develop mammary tumors [14]. These studies suggest the bations were for 60–90 min at 37°C, and washes were for involvement of Notch signaling in normal breast develop- 20 min at 37°C, with a final overnight wash at 4°C. ment, and that alterations in Notch signaling may play a role in breast cancer development [15,16]. The primary antibodies – epithelial-specific antigen and cytokeratin 18 for epithelial cells, CD10 and cytokeratin 14 Materials and methods (Novocastra, Newcastle-upon-Tyne, UK) for myoepithelial Dissociation of mammary tissue cells – were used at the dilutions indicated by the manufac- Normal breast tissue from reduction mammoplasties was turer. The Notch4 antibody was used at a dilution of 1:50 dissociated mechanically and enzymatically, as previously for immunohistochemistry and of 1:20 for immunostaining described [17]. Cells were sieved sequentially through a structures within Matrigel. AEC and DAB (Zymed) were 100 µm cell strainer and a 40 µm cell strainer (BD Falcon, used as substrates for peroxidase, and NBT/BCIP (Gibco/ Palo Alto, CA, USA) to obtain a single cell suspension. BRL, Gaithersburg, MD, USA) was used for alkaline phos- phatase. FITC-labeled and Texas-red labeled secondary Mammosphere culture antibodies (Jackson Labs, West Grove, PA, USA) were Single cells were plated on ultralow attachment plates used for fluorescent microscopy. (Corning, Acton, MA, USA) at a density of 20,000 viable cells/ml in primary culture and a density of 1000 cells/ml in Luciferase gene reporter assay passages. Cells were grown in serum-free mammary epi- MCF-7 cells were grown in
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