Developmental Lineage of Mammary Stem Cells

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R-HSA-9938206
DOI
10.3180/R-HSA-9938206.1
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CellLineagePath
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Homo sapiens
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Developmental Lineage of Mammary Stem Cells
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During embryonic development in mammals, mammary stem cells (MaSCs) are derived from embryonic non-neural surface ectoderm (Nakanoh et al. 2024, reviewed in Donovan and Cascella 2022). Embryonic ectodermal cells first produce epithelial cells of the mammary ridge in humans, which likely correspond to epithelial cells of the mammary placode in mice. However, as intermediary cell states during human mammary gland development have not been immunohistochemically characterized, and as direct extrapolation from findings in mouse may not be justified (reviewed in Gusterson and Stein 2012), only non-neural surface ectoderm cells and MaSCs have been included in this lineage and the intermediary states will be included as the data becomes available.

MaSCs have been studied in detail in mouse development, and have been much less characterized in humans. In the mouse, MaSCs are defined as those cells that are able to generate a functional mammary gland when transplanted in vivo (Shackleton et al. 2006; Stingl et al. 2006), but there is evidence that expression of certain markers in mouse MaSCs changes during different stages of mammary gland morphogenesis e.g. during pregnancy (Desgrosellier et al. 2014). Most data available on human MaSCs is derived from adult stem-like cells in human mammary glands that are able to differentiate in vitro into both myoepithelial and ductal (luminal) epithelial cells and thus are also known as mammary bipotent progenitors (MBiPs). It is uncertain how much these adult human MaSCs/MBiPs differ from embryonic and fetal MaSCs. Multiple reports agree on MaSCs residing within the basal epithelial cell subpopulation in both humans and mice, but the definitive list of markers that can be used to isolate pure MaSCs from within the basal epithelial subset has not been defined (reviewed in Phillips and Kuperwasser 2014).

Mouse MaSCs are first apparent in mammary placodes. Lef1 (Lymphoid Enhancer Binding Factor 1) is a transcription factor that binds to beta-catenin (Ctnnb1) after activation by Wnt/β-catenin signaling. The Lef1:Ctnnb1 complex plays a critical role in controlling the transcription of genes involved in mouse mammary placode formation by driving epithelial cell proliferation and differentiation during the early stages of mammary gland development (reviewed in Lindvall et al. 2007). WNT ligand Wnt10b plays an important role in the embryonic stages of mouse mammary gland development, including placode and bud formation (reviewed in Watson and Khaled 2020, Slepicka et al. 2021). Besides Wnt10b, Wnt6 and Wnt10a are also implicated in mouse mammary bud formation (reviewed in McNally and Stein 2017). Wnt4 plays a role in mouse mammary gland development during puberty and pregnancy (reviewed in Slepicka et al. 2021). Wnt4 expression is regulated by progesterone, as it is expressed in progesterone receptor-positive cells (reviewed in Tanos et al. 2012), and it acts as a paracrine mediator of progesterone signaling in the mammary gland (reviewed in McNally and Stein 2017). FGF signaling also plays a role in mammary placode formation, in particular Fgf10-mediated activation of Fgfr2b (reviewed in Mailleux et al. 2002, McNally and Stein 2017), but the FGF receptor Fgfr1 and ligands Fgf4, Fgf8, Fgf7, and Fgf17 are also expressed in the developing placode (reviewed in McNally and Stein 2017). Other signaling pathways studied in mouse that contribute to development of mammary glands and maintenance and differentiation of MaSC include Hedgehog signaling (reviewed in Lewis and Veltmaat 2004), NOTCH signaling (Bouras et al. 2008, reviewed in Edwards and Brennan 2021), and estrogen and progesterone signaling (Feng et al. 2007, reviewed in Tanos et al. 2012). The involvement of FGF10 in generation and maintenance of MaSCs appears to be conserved in humans (Qu et al. 2017, Ortiz et al. 2024).

In normal adult human breast epithelium, mammary stem cells are rare and are located in the ductal part of terminal ductal lobular units (Villadsen et al. 2007; Ginestier et al. 2007).

Recent studies indicate that the MaSC/MBiP cell population is heterogeneous, and it is likely that both early and late MaSCs exist with not completely overlapping sets of markers (Scheele et al. 2017, reviewed in Visvader and Stingl 2014 and Slepicka et al. 2021).

Literature References
PubMed ID Title Journal Year
16397499 Generation of a functional mammary gland from a single stem cell

Shackleton, M, Vaillant, F, Simpson, KJ, Stingl, J, Smyth, GK, Asselin-Labat, ML, Wu, L, Lindeman, GJ, Visvader, JE

Nature 2006
18371393 ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome

Ginestier, C, Hur, MH, Charafe-Jauffret, E, Monville, F, Dutcher, J, Brown, M, Jacquemier, J, Viens, P, Kleer, CG, Liu, S, Schott, A, Hayes, D, Birnbaum, D, Wicha, MS, Dontu, G

Cell Stem Cell 2007
24888586 Mammary stem cells and the differentiation hierarchy: current status and perspectives

Visvader, JE, Stingl, J

Genes Dev 2014
27796946 Overview of Mammary Gland Development: A Comparison of Mouse and Human

McNally, S, Stein, T

Methods Mol Biol 2017
33191272 Mammary development in the embryo and adult: new insights into the journey of morphogenesis and commitment

Watson, CJ, Khaled, WT

Development 2020
15300011 Next stop, the twilight zone: hedgehog network regulation of mammary gland development

Lewis, MT, Veltmaat, JM

J Mammary Gland Biol Neoplasia 2004
16395311 Purification and unique properties of mammary epithelial stem cells

Stingl, J, Eirew, P, Ricketson, I, Shackleton, M, Vaillant, F, Choi, D, Li, HI, Eaves, CJ

Nature 2006
34295896 Notch Signalling in Breast Development and Cancer

Edwards, A, Brennan, K

Front Cell Dev Biol 2021
17420292 Evidence for a stem cell hierarchy in the adult human breast

Villadsen, R, Fridriksdottir, AJ, Rønnov-Jessen, L, Gudjonsson, T, Rank, F, LaBarge, MA, Bissell, MJ, Petersen, OW

J Cell Biol 2007
25117682 Integrin αvβ3 drives slug activation and stemness in the pregnant and neoplastic mammary gland

Desgrosellier, JS, Lesperance, J, Seguin, L, Gozo, M, Kato, S, Franovic, A, Yebra, M, Shattil, SJ, Cheresh, DA

Dev Cell 2014
25482617 SLUG: Critical regulator of epithelial cell identity in breast development and cancer

Phillips, S, Kuperwasser, C

Cell Adh Migr 2014
17785410 Estrogen receptor-alpha expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice

Feng, Y, Manka, D, Wagner, KU, Khan, SA

Proc Natl Acad Sci U S A 2007
33082117 The molecular basis of mammary gland development and epithelial differentiation

Slepicka, PF, Somasundara, AVH, Dos Santos, CO

Semin Cell Dev Biol 2021
38427729 Human surface ectoderm and amniotic ectoderm are sequentially specified according to cellular density

Nakanoh, S, Sham, K, Ghimire, S, Mohorianu, I, Rayon, T, Vallier, L

Sci Adv 2024
28135720 Identity and dynamics of mammary stem cells during branching morphogenesis

Scheele, CL, Hannezo, E, Muraro, MJ, Zomer, A, Langedijk, NS, van Oudenaarden, A, Simons, BD, van Rheenen, J

Nature 2017
22426022 Human breast development

Gusterson, BA, Stein, T

Semin Cell Dev Biol 2012
11782400 Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo

Mailleux, AA, Spencer-Dene, B, Dillon, C, Ndiaye, D, Savona-Baron, C, Itoh, N, Kato, S, Dickson, C, Thiery, JP, Bellusci, S

Development 2002
17873348 Wnt signaling, stem cells, and the cellular origin of breast cancer

Lindvall, C, Bu, W, Williams, BO, Li, Y

Stem Cell Rev 2007
18940734 Notch signaling regulates mammary stem cell function and luminal cell-fate commitment

Bouras, T, Pal, B, Vaillant, F, Harburg, G, Asselin-Labat, ML, Oakes, SR, Lindeman, GJ, Visvader, JE

Cell Stem Cell 2008
38289401 Single-Cell Transcription Mapping of Murine and Human Mammary Organoids Responses to Female Hormones

Ortiz, JR, Lewis, SM, Ciccone, M, Chatterjee, D, Henry, S, Siepel, A, Dos Santos, CO

J Mammary Gland Biol Neoplasia 2024
33085328 Embryology, Weeks 6-8

Donovan, MF, Cascella, M

2022
22809143 ER and PR signaling nodes during mammary gland development

Tanos, T, Rojo, L, Echeverria, P, Brisken, C

Breast Cancer Res 2012
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Authored
Qiao, J  (2024-10-15)
Reviewed
Qiao, J  (2025-04-23)
Created
Orlic-Milacic, M  (2025-02-11)
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