The dynamics of murine mammary stem/progenitor cells

Abstract

The stem/progenitor cells in the murine mammary gland are a highly dynamic population of cells that are responsible for ductal elongation in puberty, homeostasis maintenance in adult, and lobulo-alveolar genesis during pregnancy. In recent years understanding the epithelial cell hierarchy within the mammary gland is becoming particularly important as these different stem/progenitor cells were perceived to be the cells of origin for various subtypes of breast cancer. Although significant advances have been made in enrichment and isolation of stem/progenitor cells by combinations of antibodies against cell surface proteins together with flow cytometry, and in identification of stem/progenitor cells with multi-lineage differentiation and self-renewal using mammary fat pad reconstitution assay and in vivo genetic labeling technique, a clear understanding of how these different stem/progenitors are orchestrated in the mammary gland is still lacking. Here we discuss the different in vivo and in vitro methods currently available for stem/progenitor identification, their associated caveats, and a possible new hierarchy model to reconcile various putative stem/progenitor cell populations identified by different research groups.

Keywords

mammary stem cell / cell hierarchy

References

[1] AlviA J, ClaytonH, JoshiC, EnverT, AshworthA, VivancoM, DaleT C, SmalleyM J (2003). Functional and molecular characterisation of mammary side population cells. Breast Cancer Res, 5(1): R1–R8

[2] Asselin-LabatM L, ShackletonM, StinglJ, VaillantF, ForrestN C, EavesC J, VisvaderJ E, LindemanG J (2006). Steroid hormone receptor status of mouse mammary stem cells. J Natl Cancer Inst, 98: 1011–1014

[3] Asselin-LabatM L, VaillantF, SheridanJ M, PalB, WuD, SimpsonE R, YasudaH, SmythG K, MartinT J, LindemanG J, VisvaderJ E (2010). Control of mammary stem cell function by steroid hormone signalling. Nature, 465(7299): 798–802

[4] BaiL, RohrschneiderL R (2010). s-SHIP promoter expression marks activated stem cells in developing mouse mammary tissue. Genes Dev, 24(17): 1882–1892

[5] BarkerN, HuchM, KujalaP, van de WeteringM, SnippertH J, van EsJ H, SatoT, StangeD E, BegthelH, van den BornM, DanenbergE, van den BrinkS, KorvingJ, AboA, PetersP J, WrightN, PoulsomR, CleversH (2010). Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell, 6(1): 25–36

[6] BarkerN, van EsJ H, JaksV, KasperM, SnippertH, ToftgårdR, CleversH (2008). Very long-term self-renewal of small intestine, colon, and hair follicles from cycling Lgr5+ve stem cells. Cold Spring Harb Symp Quant Biol, 73(0): 351–356

[7] BarkerN, van EsJ H, KuipersJ, KujalaP, van den BornM, CozijnsenM, HaegebarthA, KorvingJ, BegthelH, PetersP J, CleversH (2007). Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature, 449(7165): 1003–1007

[8] BernardoG M, LozadaK L, MiedlerJ D, HarburgG, HewittS C, MosleyJ D, GodwinA K, KorachK S, VisvaderJ E, KaestnerK H, Abdul-KarimF W, MontanoM M, KeriR A (2010). FOXA1 is an essential determinant of ERα expression and mammary ductal morphogenesis. Development, 137(12): 2045–2054

[9] BoothB W, MackD L, Androutsellis-TheotokisA, McKayR D, BoulangerC A, SmithG H (2008). The mammary microenvironment alters the differentiation repertoire of neural stem cells. Proc Natl Acad Sci USA, 105(39): 14891–14896

[10] BoulangerC A, MackD L, BoothB W, SmithG H (2007). Interaction with the mammary microenvironment redirects spermatogenic cell fate in vivo. Proc Natl Acad Sci USA, 104(10): 3871–3876

[11] BoulangerC A, WagnerK U, SmithG H (2005). Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-beta1 expression. Oncogene, 24(4): 552–560

[12] BrunoR D, SmithG H (2011). Functional characterization of stem cell activity in the mouse mammary gland. Stem Cell Rev, 7(2): 238–247

[13] de VisserK E, CiampricottiM, MichalakE M, TanD W, SpeksnijderE N, HauC S, CleversH, BarkerN, JonkersJ (2012). Developmental stage-specific contribution of LGR5(+) cells to basal and luminal epithelial lineages in the postnatal mammary gland. J Pathol, 228(3): 300–309

[14] DeomeK B, FaulkinL J Jr, BernH A, BlairP B (1959). Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. Cancer Res, 19(5): 515–520

[15] DongQ, WangD, BandyopadhyayA, GaoH, GorenaK M, HildrethK, RebelV I, WalterC A, HuangC, SunL Z (2013). Mammospheres from murine mammary stem cell-enriched basal cells: clonal characteristics and repopulating potential. Stem Cell Res (Amst), 10(3): 396–404

[16] dos SantosC O, RebbeckC, RozhkovaE, ValentineA, SamuelsA, KadiriL R, OstenP, HarrisE Y, UrenP J, SmithA D, HannonG J (2013). Molecular hierarchy of mammary differentiation yields refined markers of mammary stem cells. Proc Natl Acad Sci USA, 110(18): 7123–7130

[17] FridriksdottirA J, PetersenO W, Rønnov-JessenL (2011). Mammary gland stem cells: current status and future challenges. Int J Dev Biol, 55(7–9): 719–729

[18] FuN, LindemanG J, VisvaderJ E (2014). The mammary stem cell hierarchy. Curr Top Dev Biol, 107: 133–160

[19] JeselsohnR, BrownN E, ArendtL, KlebbaI, HuM G, KuperwasserC, HindsP W (2010). Cyclin D1 kinase activity is required for the self-renewal of mammary stem and progenitor cells that are targets of MMTV-ErbB2 tumorigenesis. Cancer Cell, 17(1): 65–76

[20] JhoE H, ZhangT, DomonC, JooC K, FreundJ N, CostantiniF (2002). Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol, 22(4): 1172–1183

[21] JoshiP A, JacksonH W, BeristainA G, Di GrappaM A, MoteP A, ClarkeC L, StinglJ, WaterhouseP D, KhokhaR (2010). Progesterone induces adult mammary stem cell expansion. Nature, 465(7299): 803–807

[22] KaantaA S, VirtanenC, SelforsL M, BruggeJ S, NeelB G (2013). Evidence for a multipotent mammary progenitor with pregnancy-specific activity. Breast Cancer Res, 15(4): R65

[23] KenneyN J, SmithG H, LawrenceE, BarrettJ C, SalomonD S (2001). Identification of stem cell units in the terminal end bud and duct of the mouse mammary gland. J Biomed Biotechnol, 1(3): 133–143

[24] KretzschmarK, WattF M (2012). Lineage tracing. Cell, 148(1–2): 33–45

[25] LimE, VaillantF, WuD, ForrestN C, PalB, HartA H, Asselin-LabatM L, GyorkiD E, WardT, PartanenA, FeleppaF, HuschtschaL I, ThorneH J, FoxS B, YanM, FrenchJ D, BrownM A, SmythG K, VisvaderJ E, LindemanG J, and the kConFab (2009). Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med, 15(8): 907–913

[26] LustigB, JerchowB, SachsM, WeilerS, PietschT, KarstenU, van de WeteringM, CleversH, SchlagP M, BirchmeierW, BehrensJ (2002). Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol, 22(4): 1184–1193

[27] ManingatP D, SenP, RijnkelsM, SunehagA L, HadsellD L, BrayM, HaymondM W (2009). Gene expression in the human mammary epithelium during lactation: the milk fat globule transcriptome. Physiol Genomics, 37(1): 12–22

[28] MatulkaL A, TriplettA A, WagnerK U (2007). Parity-induced mammary epithelial cells are multipotent and express cell surface markers associated with stem cells. Dev Biol, 303(1): 29–44

[29] MolyneuxG, GeyerF C, MagnayF A, McCarthyA, KendrickH, NatrajanR, MackayA, GrigoriadisA, TuttA, AshworthA, Reis-FilhoJ S, SmalleyM J (2010). BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell, 7(3): 403–417

[30] OakesS R, NaylorM J, Asselin-LabatM L, BlazekK D, Gardiner-GardenM, HiltonH N, KazlauskasM, PritchardM A, ChodoshL A, PfefferP L, LindemanG J, VisvaderJ E, OrmandyC J (2008). The Ets transcription factor Elf5 specifies mammary alveolar cell fate. Genes Dev, 22(5): 581–586

[31] PlaksV, BrenotA, LawsonD A, LinnemannJ R, Van KappelE C, WongK C, de SauvageF, KleinO D, WerbZ (2013). Lgr5-expressing cells are sufficient and necessary for postnatal mammary gland organogenesis. Cell Reports, 3(1): 70–78

[32] RiosA C, FuN Y, LindemanG J, VisvaderJ E (2014). In situ identification of bipotent stem cells in the mammary gland. Nature, 506(7488): 322–327

[33] RohrschneiderL R, CustodioJ M, AndersonT A, MillerC P, GuH (2005). The intron 5/6 promoter region of the ship1 gene regulates expression in stem/progenitor cells of the mouse embryo. Dev Biol, 283(2): 503–521

[34] ShackletonM, VaillantF, SimpsonK J, StinglJ, SmythG K, Asselin-LabatM L, WuL, LindemanG J, VisvaderJ E (2006). Generation of a functional mammary gland from a single stem cell. Nature, 439(7072): 84–88

[35] ShehataM, TeschendorffA, SharpG, NovcicN, RussellA, AvrilS, PraterM, EirewP, CaldasC, WatsonC J, StinglJ (2012). Phenotypic and functional characterization of the luminal cell hierarchy of the mammary gland. Breast Cancer Res, 14(5): R134

[36] SleemanK E, KendrickH, AshworthA, IsackeC M, SmalleyM J (2006). CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells. Breast Cancer Res, 8(1): R7

[37] SmithG H, ChepkoG (2001). Mammary epithelial stem cells. Microsc Res Tech, 52(2): 190–203

[38] SmithG H, MedinaD (2008). Re-evaluation of mammary stem cell biology based on in vivo transplantation. Breast Cancer Res, 10(1): 203

[39] SmithG H, StricklandP, DanielC W (2002). Putative epithelial stem cell loss corresponds with mammary growth senescence. Cell Tissue Res, 310(3): 313–320

[40] StinglJ (2009). Detection and analysis of mammary gland stem cells. J Pathol, 217(2): 229–241

[41] StinglJ, EavesC J, KuuskU, EmermanJ T (1998). Phenotypic and functional characterization in vitro of a multipotent epithelial cell present in the normal adult human breast. Differentiation, 63(4): 201–213

[42] StinglJ, EavesC J, WatsonC J (2006a). Phenotypic characterization of mouse mammary epithelial stem and progenitor cells. Breast Cancer Res, 8(Suppl 2): S5–S5

[43] StinglJ, EirewP, RicketsonI, ShackletonM, VaillantF, ChoiD, LiH I, EavesC J (2006b). Purification and unique properties of mammary epithelial stem cells. Nature, 439(7079): 993–997

[44] SumE Y, ShackletonM, HahmK, ThomasR M, O’ReillyL A, WagnerK U, LindemanG J, VisvaderJ E (2005). Loss of the LIM domain protein Lmo4 in the mammary gland during pregnancy impedes lobuloalveolar development. Oncogene, 24(30): 4820–4828

[45] TiedeB, KangY (2011). From milk to malignancy: the role of mammary stem cells in development, pregnancy and breast cancer. Cell Res, 21(2): 245–257

[46] TuZ, NinosJ M, MaZ, WangJ W, LemosM P, DespontsC, GhansahT, HowsonJ M, KerrW G (2001). Embryonic and hematopoietic stem cells express a novel SH2-containing inositol 5′-phosphatase isoform that partners with the Grb2 adapter protein. Blood, 98(7): 2028–2038

[47] VaillantF, Asselin-LabatM L, ShackletonM, ForrestN C, LindemanG J, VisvaderJ E (2008). The mammary progenitor marker CD61/beta3 integrin identifies cancer stem cells in mouse models of mammary tumorigenesis. Cancer Res, 68(19): 7711–7717

[48] VaillantF, LindemanG J, VisvaderJ E (2011). Jekyll or Hyde: does Matrigel provide a more or less physiological environment in mammary repopulating assays? Breast Cancer Res, 13(3): 108

[49] van AmerongenR, BowmanA N, NusseR (2012). Developmental stage and time dictate the fate of Wnt/β-catenin-responsive stem cells in the mammary gland. Cell Stem Cell, 11(3): 387–400

[50] Van KeymeulenA, RochaA S, OussetM, BeckB, BouvencourtG, RockJ, SharmaN, DekoninckS, BlanpainC (2011). Distinct stem cells contribute to mammary gland development and maintenance. Nature, 479(7372): 189–193

[51] VisvaderJ E (2011). Cells of origin in cancer. Nature, 469(7330): 314–322

[52] VisvaderJ E, SmithG H (2011). Murine mammary epithelial stem cells: discovery, function, and current status. Cold Spring Harb Perspect Biol, 3(2): 3

[53] WagnerK U, BoulangerC A, HenryM D, SgagiasM, HennighausenL, SmithG H (2002). An adjunct mammary epithelial cell population in parous females: its role in functional adaptation and tissue renewal. Development, 129(6): 1377–1386

[54] WangD, GaoH, BandyopadhyayA, WuA, YehI T, ChenY, ZouY, HuangC, WalterC A, DongQ, SunL Z(2014). Pubertal bisphenol a exposure alters murine mammary stem cell (MaSC) function leading to early neoplasia in regenerated glands. Cancer Prev Res (Phila), 7(4): 445–455

[55] WelmB E, TeperaS B, VeneziaT, GraubertT A, RosenJ M, GoodellM A (2002). Sca-1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population. Dev Biol, 245(1): 42–56

[56] ZengY A, NusseR (2010). Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell Stem Cell, 6(6): 568–577

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