Skip to main content

Advertisement

SpringerLink
Log in

Impact of Progesterone on Stem/Progenitor Cells in the Human Breast

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

The epithelium of the human breast is made up of a branching ductal-lobular system, which is lined by a single layer of luminal cells surrounded by a contractile basal cell layer. The co-ordinated development of stem/progenitor cells into these luminal and basal cells is fundamentally important for breast morphogenesis. The ovarian steroid hormone, progesterone, is critical in driving proliferation and normal breast development, yet progesterone analogues have also been shown to be a major driver of breast cancer risk. Studies in recent years have revealed an important role for progesterone in stimulating the mammary stem cell compartment in the mouse mammary gland, and growing evidence supports the notion that progesterone also stimulates progenitor cells in both the normal human breast and in breast cancer cells. As changes in cell type composition are one of the hallmark features of breast cancer progression, these observations have critical implications in discerning the mechanisms of how progesterone increases breast cancer risk. This review summarises recent work regarding the impact of progesterone action on the stem/progenitor cell compartment of the human breast.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

ALDH:

Aldehyde dehydrogenase

CK5:

Cytokeratin-5

CK8:

Cytokeratin-8

CK14:

Cytokeratin-14

CSC:

Cancer stem cell

DLL-1:

Delta-like 1

DLL-3:

Delta-like 3

E:

Estrogen

ER:

Estrogen receptor

GH:

Growth hormone

GHR:

Growth hormone receptor

IF:

Immunofluorescence

HRT:

Hormone replacement therapy

LRECs:

Label-retaining epithelial cells

miRNA:

microRNA

MPA:

Medroxyprogesterone acetate

P:

Progesterone

PR:

Progesterone receptor

RANKL:

Receptor activator of nuclear factor-kB ligand

SMA:

Smooth muscle actin

References

  1. Lydon JP, Ge G, Kittrell FS, Medina D, O’Malley BW. Murine mammary gland carcinogenesis is critically dependent on progesterone receptor function. Cancer Res. 1999;59(17):4276–84.

    CAS  PubMed  Google Scholar 

  2. Feinleib M. Breast cancer and artificial menopause: a cohort study. J Natl Cancer Inst. 1968;41(2):315–29.

    CAS  PubMed  Google Scholar 

  3. Trichopoulos D, MacMahon B, Cole P. Menopause and breast cancer risk. J Natl Cancer Inst. 1972;48(3):605–13.

    CAS  PubMed  Google Scholar 

  4. Brisken C. Progesterone signalling in breast cancer: a neglected hormone coming into the limelight. Nat Rev Cancer. 2013;13(6):385–96.

    Article  CAS  PubMed  Google Scholar 

  5. Collaborative Group on Hormonal Factors in Breast Cancer. Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol. 2012;13(11):1141–51.

    Article  PubMed Central  Google Scholar 

  6. Hunter DJ, Colditz GA, Hankinson SE, Malspeis S, Spiegelman D, Chen W, et al. Oral contraceptive use and breast cancer: a prospective study of young women. Cancer Epidemiol Biomarkers Prev. 2010;19(10):2496–502.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Beral V, Reeves G, Bull D, Green J. Breast cancer risk in relation to the interval between menopause and starting hormone therapy. J Natl Cancer Inst. 2011;103(4):296–305.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Chlebowski RT, Manson JE, Anderson GL, Cauley JA, Aragaki AK, Stefanick ML, et al. Estrogen plus progestin and breast cancer incidence and mortality in the women’s health initiative observational study. J Natl Cancer Inst. 2013;105(8):526–35.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Charlton BM, Rich-Edwards JW, Colditz GA, Missmer SA, Rosner BA, Hankinson SE, et al. Oral contraceptive use and mortality after 36 years of follow-up in the Nurses’ Health Study: prospective cohort study. BMJ. 2014;349.

  10. Fernandez-Valdivia R, Mukherjee A, Mulac-Jericevic B, Conneely OM, DeMayo FJ, Amato P, et al. Revealing progesterone’s role in uterine and mammary gland biology: insights from the mouse. Semin Reprod Med. 2005;23(1):22–37.

    Article  CAS  PubMed  Google Scholar 

  11. Pan H, Deng Y, Pollard JW. Progesterone blocks estrogen-induced DNA synthesis through the inhibition of replication licensing. Proc Natl Acad Sci U S A. 2006;103(38):14021–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CAJ, et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 1995;9(18):2266–78.

    Article  CAS  PubMed  Google Scholar 

  13. Brisken C, O’Malley B. Hormone action in the mammary gland. Cold Spring Harb Perspect Biol. 2010;2(12):a003178.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Howard BA, Gusterson BA. Human breast development. J Mammary Gland Biol Neoplasia. 2000;5(2):119–37.

    Article  CAS  PubMed  Google Scholar 

  15. Visvader JE. Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev. 2009;23(22):2563–77.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Polyak K, Hu M. Do myoepithelial cells hold the key for breast tumor progression? J Mammary Gland Biol Neoplasia. 2005;10(3):231–47.

    Article  PubMed  Google Scholar 

  17. Abd El-Rehim DM, Pinder SE, Paish CE, Bell J, Blamey RW, Robertson JF, et al. Expression of luminal and basal cytokeratins in human breast carcinoma. J Pathol. 2004;203(2):661–71.

    Article  PubMed  Google Scholar 

  18. Taylor-Papadimitriou J, Stampfer M, Bartek J, Lewis A, Boshell M, Lane EB, et al. Keratin expression in human mammary epithelial cells cultured from normal and malignant tissue: relation to in vivo phenotypes and influence of medium. J Cell Sci. 1989;94(Pt 3):403–13.

    PubMed  Google Scholar 

  19. Petersen OW, Polyak K. Stem cells in the human breast. Cold Spring Harb Perspect Biol. 2010;2(5):a003160.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Hilton HN, Kantimm S, Graham JD, Clarke CL. Changed lineage composition is an early event in breast carcinogenesis. Histol Histopathol. 2013;28(9):1197–204.

    PubMed  Google Scholar 

  21. Visvader JE. Cells of origin in cancer. Nature. 2011;469(7330):314–22.

    Article  CAS  PubMed  Google Scholar 

  22. Skibinski A, Kuperwasser C. The origin of breast tumor heterogeneity. Oncogene. 2015. doi:10.1038/onc.2014.475

  23. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11.

    Article  CAS  PubMed  Google Scholar 

  24. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100(7):3983–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 Is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1(5):555–67.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Ghebeh H, Sleiman G, Manogaran P, Al-Mazrou A, Barhoush E, Al-Mohanna F, et al. Profiling of normal and malignant breast tissue show CD44high/CD24low phenotype as a predominant stem/progenitor marker when used in combination with Ep-CAM/CD49f markers. BMC Cancer. 2013;13(1):289.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Villadsen R, Fridriksdottir AJ, Rønnov-Jessen L, Gudjonsson T, Rank F, LaBarge MA, et al. Evidence for a stem cell hierarchy in the adult human breast. J Cell Biol. 2007;177(1):87–101.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Raouf A, Zhao Y, To K, Stingl J, Delaney A, Barbara M, et al. Transcriptome analysis of the normal human mammary cell commitment and differentiation process. Cell Stem Cell. 2008;3(1):109–18.

    Article  CAS  PubMed  Google Scholar 

  29. Nakshatri H, Srour EF, Badve S. Breast cancer stem cells and intrinsic subtypes: controversies rage on. Curr Stem Cell Res Ther. 2009;4(1):50–60.

    Article  CAS  PubMed  Google Scholar 

  30. Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, et al. Generation of a functional mammary gland from a single stem cell. Nature. 2006;439(7072):84–8.

    Article  CAS  PubMed  Google Scholar 

  31. Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D, et al. Purification and unique properties of mammary epithelial stem cells. Nature. 2006;439(7079):993–7.

    CAS  PubMed  Google Scholar 

  32. Eirew P, Stingl J, Raouf A, Turashvili G, Aparicio S, Emerman JT, et al. A method for quantifying normal human mammary epithelial stem cells with in vivo regenerative ability. Nat Med. 2008;14(12):1384–9.

    Article  CAS  PubMed  Google Scholar 

  33. Van Keymeulen A, Blanpain C. Tracing epithelial stem cells during development, homeostasis, and repair. J Cell Biol. 2012;197(5):575–84.

    Article  PubMed Central  PubMed  Google Scholar 

  34. van Amerongen R, Bowman Angela N, Nusse R. Developmental stage and time dictate the fate of wnt/β-catenin-responsive stem cells in the mammary gland. Cell Stem Cell. 2012;11(3):387–400.

    Article  PubMed  Google Scholar 

  35. Van Keymeulen A, Rocha AS, Ousset M, Beck B, Bouvencourt G, Rock J, et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature. 2011;479(7372):189–93.

    Article  PubMed  Google Scholar 

  36. Rios AC, Fu NY, Lindeman GJ, Visvader JE. In situ identification of bipotent stem cells in the mammary gland. Nature. 2014;506(7488):322–7.

    Article  CAS  PubMed  Google Scholar 

  37. Sutherland RL, Prall OW, Watts CK, Musgrove EA. Estrogen and progestin regulation of cell cycle progression. J Mammary Gland Biol Neoplasia. 1998;3(1):63–72.

    Article  CAS  PubMed  Google Scholar 

  38. Asselin-Labat ML, Vaillant F, Sheridan JM, Pal B, Wu D, Simpson ER, et al. Control of mammary stem cell function by steroid hormone signalling. Nature. 2010;465(7299):798–802.

    Article  CAS  PubMed  Google Scholar 

  39. Joshi PA, Jackson HW, Beristain AG, Di Grappa MA, Mote P, Clarke C, et al. Progesterone induces adult mammary stem cell expansion. Nature. 2010;465(7299):803–7.

    Article  CAS  PubMed  Google Scholar 

  40. Fata JE, Kong Y-Y, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell. 2000;103(1):41–50.

    Article  CAS  PubMed  Google Scholar 

  41. Brisken C, Heineman A, Chavarria T, Elenbaas B, Tan J, Dey SK, et al. Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling. Genes Dev. 2000;14(6):650–4.

    PubMed Central  CAS  PubMed  Google Scholar 

  42. Rajaram RD, Buric D, Caikovski M, Ayyanan A, Rougemont J, Shan J, et al. Progesterone and Wnt4 control mammary stem cells via myoepithelial crosstalk. EMBO J. 2015;34(5):641–52.

    Article  CAS  PubMed  Google Scholar 

  43. Shiah Y-J, Tharmapalan P, Casey Alison E, Joshi Purna A, McKee Trevor D, Jackson Hartland W, et al. A progesterone-CXCR4 axis controls mammary progenitor cell fate in the adult gland CXCR4 function in mammary progenitors. Stem Cell Rep. 2015;4(3):313–22.

    Article  CAS  Google Scholar 

  44. Pike MC, Spicer DV, Dahmoush L, Press MF. Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev. 1993;15(1):17–35.

    CAS  PubMed  Google Scholar 

  45. Barnes DM, Newman LA. Pregnancy-associated breast cancer: a literature review. Surg Clin North Am. 2007;87(2):417–30.

    Article  PubMed  Google Scholar 

  46. Graham JD, Mote PA, Salagame U, van Dijk JH, Balleine RL, Huschtscha LI, et al. DNA replication licensing and progenitor numbers are increased by progesterone in normal human breast. Endocrinology. 2009;150(7):3318–26.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 2003;17(10):1253–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Arendt LM, St. Laurent J, Wronski A, Caballero S, Lyle SR, Naber SP, et al. Human breast progenitor cell numbers are regulated by WNT and TBX3. PLoS One. 2014;9(10), e111442.

    Article  PubMed Central  PubMed  Google Scholar 

  49. Hilton HN, Santucci N, Silvestri A, Kantimm S, Huschtscha LI, Graham JD, et al. Progesterone stimulates progenitor cells in normal human breast and breast cancer cells. Breast Cancer Res Treat. 2014;143(3):423–33.

    Article  CAS  PubMed  Google Scholar 

  50. Bachelard-Cascales E, Chapellier M, Delay E, Pochon G, Voeltzel T, Puisieux A, et al. The CD10 enzyme is a key player to identify and regulate human mammary stem cells. Stem Cells. 2010;28(6):1081–8.

    Article  CAS  PubMed  Google Scholar 

  51. Keller PJ, Arendt LM, Skibinski A, Logvinenko T, Klebba I, Dong S, et al. Defining the cellular precursors to human breast cancer. Proc Natl Acad Sci U S A. 2012;109(8):2772–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Garbe JC, Pepin F, Pelissier FA, Sputova K, Fridriksdottir AJ, Guo DE, et al. Accumulation of multipotent progenitors with a basal differentiation bias during aging of human mammary epithelia. Cancer Res. 2012;72(14):3687–701.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Stingl J, Eaves CJ, Kuusk U, Emerman JT. Phenotypic and functional characterization in vitro of a multipotent epithelial cell present in the normal adult human breast. Differentiation. 1998;63(4):201–13.

    Article  CAS  PubMed  Google Scholar 

  54. Palafox M, Ferrer I, Pellegrini P, Vila S, Hernandez-Ortega S, Urruticoechea A, et al. RANK induces epithelial–mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Cancer Res. 2012;72(11):2879–88.

    Article  CAS  PubMed  Google Scholar 

  55. Tanos T, Sflomos G, Echeverria PC, Ayyanan A, Gutierrez M, Delaloye J-F, et al. Progesterone/RANKL is a major regulatory axis in the human breast. Sci Transl Med. 2013;5(182):182ra155.

    Google Scholar 

  56. Pardo I, Lillemoe H, Blosser R, Choi M, Sauder C, Doxey D, et al. Next-generation transcriptome sequencing of the premenopausal breast epithelium using specimens from a normal human breast tissue bank. Breast Cancer Res. 2014;16(2):R26.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Hu H, Wang J, Gupta A, Shidfar A, Branstetter D, Lee O, et al. RANKL expression in normal and malignant breast tissue responds to progesterone and is up-regulated during the luteal phase. Breast Cancer Res Treat. 2014;146(3):515–23.

    Article  CAS  PubMed  Google Scholar 

  58. Wang J, Gupta A, Hu H, Chatterton RT, Clevenger CV, Khan SA. Comment on “Progesterone/RANKL is a major regulatory axis in the human breast”. Sci Transl Med. 2013;5(215):215le214.

    Google Scholar 

  59. Lombardi S, Honeth G, Ginestier C, Shinomiya I, Marlow R, Buchupalli B, et al. Growth hormone is secreted by normal breast epithelium upon progesterone stimulation and increases proliferation of stem/progenitor cells. Stem Cell Rep. 2014;2(6):780–93.

    Article  CAS  Google Scholar 

  60. Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res. 2004;6(6):R605–15.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Ghatge R, Jacobsen B, Schittone S, Horwitz K. The progestational and androgenic properties of medroxyprogesterone acetate: gene regulatory overlap with dihydrotestosterone in breast cancer cells. Breast Cancer Res. 2005;7(6):R1036–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Horwitz KB, Dye WW, Harrell JC, Kabos P, Sartorius CA. Rare steroid receptor-negative basal-like tumorigenic cells in luminal subtype human breast cancer xenografts. Proc Natl Acad Sci U S A. 2008;105(15):5774–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Meier-Abt F, Milani E, Roloff T, Brinkhaus H, Duss S, Meyer D, et al. Parity induces differentiation and reduces Wnt/Notch signaling ratio and proliferation potential of basal stem/progenitor cells isolated from mouse mammary epithelium. Breast Cancer Res. 2013;15(2):R36.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Meier-Abt F, Brinkhaus H, Bentires-Alj M. Early but not late pregnancy induces lifelong reductions in the proportion of mammary progesterone sensing cells and epithelial Wnt signaling. Breast Cancer Res. 2014;16(2):402.

    Article  PubMed Central  PubMed  Google Scholar 

  65. Meier-Abt F, Bentires-Alj M. How pregnancy at early age protects against breast cancer. Trends Mol Med. 2014;20(3):143–53.

    Article  PubMed  Google Scholar 

  66. Sartorius CA, Harvell DM, Shen T, Horwitz KB. Progestins initiate a luminal to myoepithelial switch in estrogen-dependent human breast tumors without altering growth. Cancer Res. 2005;65(21):9779–88.

    Article  CAS  PubMed  Google Scholar 

  67. Kabos P, Haughian J, Wang X, Dye W, Finlayson C, Elias A, et al. Cytokeratin 5 positive cells represent a steroid receptor negative and therapy resistant subpopulation in luminal breast cancers. Breast Cancer Res Treat. 2011;128(1):45–55.

    Article  CAS  PubMed  Google Scholar 

  68. Cittelly DM, Finlay-Schultz J, Howe EN, Spoelstra NS, Axlund SD, Hendricks P, et al. Progestin suppression of miR-29 potentiates dedifferentiation of breast cancer cells via KLF4. Oncogene. 2013;32(20):2555–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Li M, Zhao D, Ma G, Zhang B, Fu X, Zhu Z, et al. Upregulation of ATBF1 by progesterone-PR signaling and its functional implication in mammary epithelial cells. Biochem Biophys Res Commun. 2013;430(1):358–63.

    Article  CAS  PubMed  Google Scholar 

  70. Axlund S, Yoo B, Rosen R, Schaack J, Kabos P, LaBarbera D, et al. Progesterone-inducible cytokeratin 5-positive cells in luminal breast cancer exhibit progenitor properties. Horm Cancer. 2013;4(1):36–49.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Vares G, Cui X, Wang B, Nakajima T, Nenoi M. Generation of breast cancer stem cells by steroid hormones in irradiated human mammary cell lines. PLoS One. 2013;8(10), e77124.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Finlay-Schultz J, Cittelly DM, Hendricks P, Patel P, Kabos P, Jacobsen BM, et al. Progesterone downregulation of miR-141 contributes to expansion of stem-like breast cancer cells through maintenance of progesterone receptor and Stat5a. Oncogene. 2014;0.

  73. Choudhury S, Almendro V, Merino Vanessa F, Wu Z, Maruyama R, Su Y, et al. Molecular profiling of human mammary gland links breast cancer risk to a p27+ cell population with progenitor characteristics. Cell Stem Cell. 2013;13(1):117–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Horwitz KB, Sartorius CA. Progestins in hormone replacement therapies reactivate cancer stem cells in women with preexisting breast cancers: a hypothesis. J Clin Endocrinol Metab. 2008;93(9):3295–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Lambrinoudaki I. Progestogens in postmenopausal hormone therapy and the risk of breast cancer. Maturitas. 2014;77(4):311–7.

    Article  CAS  PubMed  Google Scholar 

  76. Chlebowski RT, Rohan TE, Manson JE, et al. Breast cancer after use of estrogen plus progestin and estrogen alone: analyses of data from 2 women’s health initiative randomized clinical trials. JAMA Oncol. 2015;1(3):296–305.

    Article  PubMed  Google Scholar 

  77. Joshi PA, Goodwin PJ, Khokha R. Progesterone exposure and breast cancer risk: understanding the biological roots. JAMA Oncol. 2015;1(3):283–5.

    Article  PubMed  Google Scholar 

  78. Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature. 2010;468(7320):103–7.

    Article  CAS  PubMed  Google Scholar 

  79. Schramek D, Leibbrandt A, Sigl V, Kenner L, Pospisilik JA, Lee HJ, et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature. 2010;468(7320):98–102.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Cochrane DR, Spoelstra NS, Richer JK. The role of miRNAs in progesterone action. Mol Cell Endocrinol. 2012;357(1–2):50–9.

    Article  CAS  PubMed  Google Scholar 

  81. Cochrane DR, Jacobsen BM, Connaghan KD, Howe EN, Bain DL, Richer JK. Progestin regulated miRNAs that mediate progesterone receptor action in breast cancer. Mol Cell Endocrinol. 2012;355(1):15–24.

    Article  CAS  PubMed  Google Scholar 

  82. Yu F, Li J, Chen H, Fu J, Ray S, Huang S, et al. Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion. Oncogene. 2011;30(18):2161–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Richer JK, Jacobsen BM, Manning NG, Abel MG, Wolf DM, Horwitz KB. Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J Biol Chem. 2002;277(7):5209–18.

    Article  CAS  PubMed  Google Scholar 

  84. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10(5):593–601.

    Article  CAS  PubMed  Google Scholar 

  85. Asselin-Labat ML, Shackleton M, Stingl J, Vaillant F, Forrest NC, Eaves CJ, et al. Steroid hormone receptor status of mouse mammary stem cells. J Natl Cancer Inst. 2006;98(14):1011–4.

    Article  CAS  PubMed  Google Scholar 

  86. Booth BW, Smith GH. Estrogen receptor-α and progesterone receptor are expressed in label-retaining mammary epithelial cells that divide asymmetrically and retain their template DNA strands. Breast Cancer Res. 2006;8:R49.

    Article  PubMed Central  PubMed  Google Scholar 

  87. Smith GH. Label-retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template DNA strands. Development. 2005;132(4):681–7.

    Article  CAS  PubMed  Google Scholar 

  88. Clarke RB, Spence K, Anderson E, Howell A, Okano H, Potten CS. A putative human breast stem cell population is enriched for steroid receptor-positive cells. Dev Biol. 2005;277(2):443–56.

    Article  CAS  PubMed  Google Scholar 

  89. Hilton HN, Graham JD, Kantimm S, Santucci N, Cloosterman D, Huschtscha LI, et al. Progesterone and estrogen receptors segregate into different cell subpopulations in the normal human breast. Mol Cell Endocrinol. 2012;361(1–2):191–201.

    Article  CAS  PubMed  Google Scholar 

  90. Taylor D, Pearce CL, Hovanessian-Larsen L, Downey S, Spicer DV, Bartow S, et al. Progesterone and estrogen receptors in pregnant and premenopausal non-pregnant normal human breast. Breast Cancer Res Treat. 2009;118(1):161–8.

    Article  CAS  PubMed  Google Scholar 

  91. McKeon F. p63 and the epithelial stem cell: more than status quo? Genes Dev. 2004;18(5):465–9.

    Article  CAS  PubMed  Google Scholar 

  92. Yalcin-Ozuysal O, Fiche M, Guitierrez M, Wagner KU, Raffoul W, Brisken C. Antagonistic roles of Notch and p63 in controlling mammary epithelial cell fates. Cell Death Differ. 2010;17(10):1600–12.

    Article  CAS  PubMed  Google Scholar 

  93. Honeth G, Lombardi S, Ginestier C, Hur M, Marlow R, Buchupalli B, et al. Aldehyde dehydrogenase and estrogen receptor define a hierarchy of cellular differentiation in the normal human mammary epithelium. Breast Cancer Res. 2014;16(3):R52.

    Article  PubMed Central  PubMed  Google Scholar 

  94. Stingl J, Eaves CJ, Zandieh I, Emerman JT. Characterization of bipotent mammary epithelial progenitor cells in normal adult human breast tissue. Breast Cancer Res Treat. 2001;67(2):93–109.

    Article  CAS  PubMed  Google Scholar 

  95. Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell. 2007;11(3):259–73.

    Article  CAS  PubMed  Google Scholar 

  96. Beleut M, Rajaram RD, Caikovski M, Ayyanan A, Germano D, Choi Y, et al. Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland. Proc Natl Acad Sci U S A. 2010;107(7):2989–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

HNH is supported by a Postdoctoral Fellowship co-funded by the Cure Cancer Australia Foundation and the National Breast Cancer Foundation. CLC is a research fellow of the National Health and Medical Research Council of Australia.

Author information

Authors and Affiliations

  1. Centre for Cancer Research, Westmead Millennium Institute, University of Sydney Medical School, Westmead, NSW, Australia

    Heidi N. Hilton & Christine L. Clarke

Authors
  1. Heidi N. Hilton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christine L. Clarke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Heidi N. Hilton.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hilton, H.N., Clarke, C.L. Impact of Progesterone on Stem/Progenitor Cells in the Human Breast. J Mammary Gland Biol Neoplasia 20, 27–37 (2015). https://doi.org/10.1007/s10911-015-9339-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10911-015-9339-y

Keywords

Search

Navigation