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Hormone-Sensing Mammary Epithelial Progenitors: Emerging Identity and Hormonal Regulation

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Abstract

The hormone-sensing mammary epithelial cell (HS-MEC—expressing oestrogen receptor-alpha (ERα) and progesterone receptor (PGR)) is often represented as being terminally differentiated and lacking significant progenitor activity after puberty. Therefore while able to profoundly influence the proliferation and function of other MEC populations, HS-MECs are purported not to respond to sex hormone signals by engaging in significant cell proliferation during adulthood. This is a convenient and practical simplification that overshadows the sublime, and potentially critical, phenotypic plasticity found within the adult HS-MEC population. This concept is exemplified by the large proportion (~80 %) of human breast cancers expressing PGR and/or ERα, demonstrating that HS-MECs clearly proliferate in the context of breast cancer. Understanding how HS-MEC proliferation and differentiation is driven could be key to unraveling the mechanisms behind uncontrolled HS-MEC proliferation associated with ERα- and/or PGR-positive breast cancers. Herein we review evidence for the existence of a HS-MEC progenitor and the emerging plasticity of the HS-MEC population in general. This is followed by an analysis of hormones other than oestrogen and progesterone that are able to influence HS-MEC proliferation and differentiation: androgens, prolactin and transforming growth factor-beta1.

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Abbreviations

ALDH:

Alcohol Dehydrogenase

AREG:

Aregulin

AR:

Androgen Receptor

BER-EP4:

Epithelial-Specific Antigen (also known as EPCAM)

CALLA:

Common Acute Lymphoblastic Leukaemia antigen (also known as CD10)

C/EBPβ:

CAAT/Enhancer Binding Protein

CD49b:

Cluster of Differentiation 49b (also known as alpha-2 Integrin)

CD49f:

Cluster of Differentiation 49f (also known as alpha-6 Integrin)

ELF5:

E74-like Protein 5

EGF:

Epidermal Growth Factor

EMT:

Epithelial to Mesenchymal Transition

FACS:

Fluorescence-Activated Cell Sorting

FOXA1:

Forkhead box A1

GATA3:

GATA-binding protein 3

GREB1:

Growth Regulated by Estrogen in the Breast 1

GH:

Growth Hormone

HS-MECs:

Hormone-Sensing Mammary Epithelial Cells

IGF2:

Insulin-like Growth Factor 2

JAK2:

Janus Kinase 2

LRH1:

Liver Receptor Homolog 1

LA:

Lobuloalveolar Unit

MMPs:

Matrix Metalloproteinases

MMTV:

Mouse Mammary Tumour Virus

MUC1:

Mucin 1

ERα:

Oestrogen Receptor-alpha

PELP1:

Proline, Glutamate and Leucine Rich Protein 1

PGR:

Progesterone Receptor

PRLR:

Prolactin Receptor

RANKL:

Receptor Activator of Nuclear factor Kappa-B Ligand

RUNX:

RUNT-related Transcription Factor

SCA1:

Stem Cells Antigen 1 (also known as LY6A/E)

SMAD:

Mothers Against Decapentaplegic

SP:

Side Population

STAT5:

Signal Transducer and Activator of Transcription 5

TBX3:

T-box Transcription Factor 3

TDLU:

Terminal Ductal Lobule Unit

TOX3:

TOX High Mobility Group Box Family Member 3

TGFβ:

Transforming Growth Factor-beta

WAP:

Whey-Acidic Protein

WNT:

Wingless-type MMTV Integration Site Family Member

References

  1. 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;14:650–4.

    PubMed Central  CAS  PubMed  Google Scholar 

  2. Aupperlee MD, Leipprandt JR, Bennett JM, Schwartz RC, Haslam SZ. Amphiregulin mediates progesterone-induced mammary ductal development during puberty. Breast Cancer Res. 2013;15:R44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Mukherjee A, Soyal SM, Li J, Ying Y, He B, DeMayo FJ, et al. Targeting RANKL to a specific subset of murine mammary epithelial cells induces ordered branching morphogenesis and alveologenesis in the absence of progesterone receptor expression. FASEB J. 2010;24:4408–19.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat M-L, et al. Generation of a functional mammary gland from a single stem cell. Nat Cell Biol. 2006;439:84–8.

    CAS  Google Scholar 

  5. 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;439:993–7.

    CAS  PubMed  Google Scholar 

  6. Sleeman KE, Kendrick H, Robertson D, Isacke CM, Ashworth A, Smalley MJ. Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary gland. J Cell Biol. 2007;176:19–26.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Shiah Y-J, Tharmapalan P, Casey AE, Joshi PA, McKee TD, Jackson HW, et al. A progesterone-CXCR4 axis controls mammary progenitor cell fate in the adult gland. Stem Cell Rep. 2015;4:313–22.

    Article  CAS  Google Scholar 

  9. Mastroianni M, Kim S, Kim YC, Esch A, Wagner C, Alexander CM. Wnt signaling can substitute for estrogen to induce division of ERα-positive cells in a mouse mammary tumor model. Cancer Lett. 2010;289:23–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Cardiff RD. Are the TDLU of the human the same as the LA of mice? J Mammary Gland Biol Neoplasia. 1998;3:3–5.

    Article  CAS  PubMed  Google Scholar 

  11. Lain AR, Creighton CJ, Conneely OM. Research resource: progesterone receptor targetome underlying mammary gland branching morphogenesis. Mol Endocrinol. 2013;27:1743–61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Fata JE, Chaudhary V, Khokha R. Cellular turnover in the mammary gland is correlated with systemic levels of progesterone and not 17beta-estradiol during the estrous cycle. Biol Reprod. 2001;65:680–8.

    Article  CAS  PubMed  Google Scholar 

  13. Robinson GW, McKnight RA, Smith GH, Hennighausen L. Mammary epithelial cells undergo secretory differentiation in cycling virgins but require pregnancy for the establishment of terminal differentiation. Development. 1995;121:2079–90.

    CAS  PubMed  Google Scholar 

  14. Going JJ, Anderson TJ, Battersby S, MacIntyre CC. Proliferative and secretory activity in human breast during natural and artificial menstrual cycles. Am J Pathol. 1988;130:193–204.

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Potten CS, Watson RJ, Williams GT, Tickle S, Roberts SA, Harris M, et al. The effect of age and menstrual cycle upon proliferative activity of the normal human breast. Br J Cancer. 1988;58:163–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Anderson E, Clarke RB, Howell A. Estrogen responsiveness and control of normal human breast proliferation. J Mammary Gland Biol Neoplasia. 1998;3:23–35.

    Article  CAS  PubMed  Google Scholar 

  17. 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;146:515–23.

    Article  CAS  PubMed  Google Scholar 

  18. Cardiff R, Anver M, Boivin G, Bosenberg M, Maronpot R, Molinolo A, et al. Precancer in mice: animal models used to understand, prevent, and treat human precancers. Toxicol Pathol. 2006;34:699–707.

    Article  PubMed  Google Scholar 

  19. Calaf G, Alvarado M, Bonney G, Amfoh K, Russo J. Influence of lobular development on breast epithelial-cell proliferation and steroid-hormone receptor content. Int J Oncol. 1995;7:1285–8.

    CAS  PubMed  Google Scholar 

  20. Russo J, Russo IH. Development of the human breast. Maturitas. 2004;49:2–15.

    Article  CAS  PubMed  Google Scholar 

  21. Russo IH, Russo J. Role of hormones in mammary cancer initiation and progression. J Mammary Gland Biol Neoplasia. 1998;3:49–61.

    Article  CAS  PubMed  Google Scholar 

  22. Russo J, Ao X, Grill C, Russo IH. Pattern of distribution of cells positive for estrogen receptor alpha and progesterone receptor in relation to proliferating cells in the mammary gland. Breast Cancer Res Treat. 1999;53:217–27.

    Article  CAS  PubMed  Google Scholar 

  23. Fendrick JL, Raafat AM, Haslam SZ. Mammary gland growth and development from the postnatal period to postmenopause: ovarian steroid receptor ontogeny and regulation in the mouse. J Mammary Gland Biol Neoplasia. 1998;3:7–22.

    Article  CAS  PubMed  Google Scholar 

  24. Li S, Han B, Liu G, Li S, Ouellet J, Labrie F, et al. Immunocytochemical localization of sex steroid hormone receptors in normal human mammary gland. J Histochem Cytochem. 2010;58:509–15.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. 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;277:443–56.

    Article  CAS  PubMed  Google Scholar 

  26. Booth BW, Boulanger CA, Smith GH. Selective segregation of DNA strands persists in long label retaining mammary cells during pregnancy. Breast Cancer Res. 2008;10:R90.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  27. Booth BW, Smith GH. Breast Cancer Res. 2006;8:R49.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  28. Santagata S, Thakkar A, Ergonul A, Wang B, Woo T, Hu R, et al. Taxonomy of breast cancer based on normal cell phenotype predicts outcome. J Clin Invest. 2014;124:859–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Shoker BS, Jarvis C, Sibson DR, Walker C, Sloane JP. Oestrogen receptor expression in the normal and pre-cancerous breast. J Pathol. 1999;188:237–44.

    Article  CAS  PubMed  Google Scholar 

  30. Ewan KBR, Oketch-Rabah HA, Ravani SA, Shyamala G, Moses HL, Barcellos-Hoff MH. Proliferation of estrogen receptor-alpha-positive mammary epithelial cells is restrained by transforming growth factor-beta1 in adult mice. Am J Pathol. 2005;167:409–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. 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;107:2989–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. De Silva D, Kunasegaran K, Ghosh S, Pietersen AM. Transcriptome analysis of the hormone-sensing cells in mammary epithelial reveals dynamic changes in early pregnancy. BMC Dev Biol. 2015;15:a003178.

    Article  CAS  Google Scholar 

  33. Tornillo G, Smalley MJ. ERrrr…Where are the progenitors? Hormone receptors and mammary cell heterogeneity. J Mammary Gland Biol Neoplasia. 2015. doi:10.1007/s10911-015-9336-1

  34. Li W, Ferguson BJ, Khaled WT, Tevendale M, Stingl J, Poli V, et al. PML depletion disrupts normal mammary gland development and skews the composition of the mammary luminal cell progenitor pool. Proc Natl Acad Sci. 2009;106:4725–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Kunasegaran K, Ho V, Chang TH-T, De Silva D, Bakker ML, Christoffels VM, et al. Transcriptional repressor Tbx3 is required for the hormone-sensing cell lineage in mammary epithelium. PLoS ONE. 2014;9:e110191.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  36. Shehata M, Teschendorff A, Sharp G, Novcic N, Russell IA, Avril S, et al. Phenotypic and functional characterisation of the luminal cell hierarchy of the mammary gland. Breast Cancer Res. 2012;14:R134.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Joshi PA, Waterhouse PD, Kannan N, Narala S, Fang H, Di Grappa MA, et al. RANK signaling amplifies WNT-responsive mammary progenitors through R-SPONDIN1. Stem Cell Rep. 2015;5:31–44.

    Article  CAS  Google Scholar 

  38. Choudhury S, Almendro V, Merino VF, 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;13:117–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. 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;16:1–14.

    Article  CAS  Google Scholar 

  40. Welm BE, Tepera SB, Venezia T, Graubert TA, Rosen JM, Goodell MA. Sca-1pos cells in the mouse mammary gland represent an enriched progenitor cell population. Dev Biol. 2002;245:42–56.

    Article  CAS  PubMed  Google Scholar 

  41. Clayton H, Titley I, Vivanco MD. Growth and differentiation of progenitor/stem cells derived from the human mammary gland. Exp Cell Res. 2004;297:444–60.

    Article  CAS  PubMed  Google Scholar 

  42. Alvi AJ, Clayton H, Joshi C, Enver T, Ashworth A, Vivanco MDM, et al. Functional and molecular characterisation of mammary side population cells. Breast Cancer Res. 2003;5:R1–8.

    Article  PubMed Central  PubMed  Google Scholar 

  43. Pellegrini P, Cordero A, Gallego MI, Dougall WC, Purificación M, Pujana MA, et al. Constitutive activation of RANK disrupts mammary cell fate leading to tumorigenesis. Stem Cells. 2013;31:1954–65.

    Article  PubMed  CAS  Google Scholar 

  44. Tarulli GA, De Silva D, Ho V, Kunasegaran K, Ghosh K, Tan BC, et al. Hormone-sensing cells require Wip1 for paracrine stimulation in normal and premalignant mammary epithelium. Breast Cancer Res. 2013;15:R10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Regan JL, Kendrick H, Magnay F-A, Vafaizadeh V, Groner B, Smalley MJ. c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer. Oncogene. 2012;31:869–83.

    Article  CAS  PubMed  Google Scholar 

  46. Smith GH, Vonderhaar BK, Graham DE, Medina D. Expression of pregnancy-specific genes in preneoplastic mouse mammary tissues from virgin mice. Cancer Res. 1984;44:3426–37.

    CAS  PubMed  Google Scholar 

  47. Ferguson DJ. Ultrastructural characterisation of the proliferative (stem?) cells within the parenchyma of the normal “resting” breast. Virchows Arch A Pathol Anat Histopathol. 1985;407:379–85.

    Article  CAS  PubMed  Google Scholar 

  48. Chepko G, Smith GH. Three division-competent, structurally-distinct cell populations contribute to murine mammary epithelial renewal. Tissue Cell. 1997;29:239–53.

    Article  CAS  PubMed  Google Scholar 

  49. Smith GH, Chepko G. Mammary epithelial stem cells. Microsc Res Tech. 2001;52:190–203.

    Article  CAS  PubMed  Google Scholar 

  50. 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;361:191–201.

    Article  CAS  PubMed  Google Scholar 

  51. Hilton HN, Doan TB, Graham JD, et al. Acquired convergence of hormone signaling in breast cancer: ER and PR transition from functionally distinct in normal breast to predictors of metastatic disease. Oncotarget. 2014;5(18):8651–64.

    Article  PubMed Central  PubMed  Google Scholar 

  52. Shyamala G, Chou YC, Louie SG, Guzman RC, Smith GH, Nandi S. Cellular expression of estrogen and progesterone receptors in mammary glands: regulation by hormones, development and aging. J Steroid Biochem Mol Biol. 2002;80:137–48.

    Article  CAS  PubMed  Google Scholar 

  53. 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;98:1011–4.

    Article  CAS  PubMed  Google Scholar 

  54. Prater MD, Petit V, Alasdair Russell I, Giraddi RR, Shehata M, Menon S, et al. Mammary stem cells have myoepithelial cell properties. Nat Cell Biol. 2014;16:942–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Brisken C, Ataca D. Endocrine hormones and local signals during the development of the mouse mammary gland. Wiley Interdiscip Rev Dev Biol. 2015;4(3):181–95.

    Article  CAS  PubMed  Google Scholar 

  56. Mohammed H, Russell IA, Stark R, Rueda OM, Hickey TE, Tarulli GA, et al. Progesterone receptor modulates ERα action in breast cancer. Nature. 2015;523:313–7.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  58. Tanos T, Rojo L, Echeverria P, Brisken C. ER and PR signaling nodes during mammary gland development. Breast Cancer Res. 2012;14:210.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Brisken C, Kaur S, Chavarria TE, Binart N, Sutherland RL, Weinberg RA, et al. Prolactin controls mammary gland development via direct and indirect mechanisms. Dev Biol. 1999;210:96–106.

    Article  CAS  PubMed  Google Scholar 

  60. Miyoshi K. Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium. J Cell Biol. 2001;155:531–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Santos SJ, Haslam SZ, Conrad SE. Signal transducer and activator of transcription 5a mediates mammary ductal branching and proliferation in the nulliparous mouse. Endocrinology. 2010;151:2876–85.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Santos SJ, Haslam SZ, Conrad SE. Estrogen and progesterone are critical regulators of Stat5a expression in the mouse mammary gland. Endocrinology. 2008;149:329–38.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Wood CE, Branstetter D, Jacob AP, Cline JM, Register TC, Rohrbach K, et al. Progestin effects on cell proliferation pathways in the postmenopausal mammary gland. Breast Cancer Res. 2013;15:R62.

    Article  PubMed Central  PubMed  Google Scholar 

  64. Srivastava S, Matsuda M, Hou Z, Bailey JP, Kitazawa R, Herbst MP, et al. Receptor activator of NF- B ligand induction via Jak2 and Stat5a in mammary epithelial cells. J Biol Chem. 2003;278:46171–8.

    Article  CAS  PubMed  Google Scholar 

  65. Obr AE, Grimm SL, Bishop KA, Pike JW, Lydon JP, Edwards DP. Progesterone receptor and Stat5 signaling cross talk through RANKL in mammary epithelial cells. Mol Endocrinol. 2013;27:1808–24.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Brisken C, Ayyannan A, Nguyen C, Heineman A, Reinhardt F, Tan J, et al. IGF-2 is a mediator of prolactin-induced morphogenesis in the breast. Dev Cell. 2002;3:877–87.

    Article  CAS  PubMed  Google Scholar 

  67. Hovey RC. Local insulin-like growth factor-II mediates prolactin-induced mammary gland development. Mol Endocrinol. 2002;17:460–71.

    Article  PubMed  CAS  Google Scholar 

  68. Nevalainen MT, Xie J, Bubendorf L, Wagner K-U, Rui H. Basal activation of transcription factor signal transducer and activator of transcription (Stat5) in nonpregnant mouse and human breast epithelium. Mol Endocrinol (Baltimore, Md). 2002;16:1108–24.

    Article  CAS  Google Scholar 

  69. Buser AC, Gass-Handel EK, Wyszomierski SL, Doppler W, Leonhardt SA, Schaack J, et al. Progesterone receptor repression of prolactin/signal transducer and activator of transcription 5-mediated transcription of the β-casein gene in mammary epithelial cells. Mol Endocrinol. 2007;21:106–25.

    Article  CAS  PubMed  Google Scholar 

  70. Gallego MI, Binart N, Robinson GW, Okagaki R, Coschigano KT, Perry J, et al. Prolactin, growth hormone, and epidermal growth factor activate Stat5 in different compartments of mammary tissue and exert different and overlapping developmental effects. Dev Biol. 2001;229:163–75.

    Article  CAS  PubMed  Google Scholar 

  71. O’Leary KA, Jallow F, Rugowski DE, Sullivan R, Sinkevicius KW, Greene GL, et al. Prolactin activates ER in the absence of ligand in female mammary development and carcinogenesis in vivo. Endocrinology. 2013;154:4483–92.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  72. Dong J, Tong T, Reynado AM, Rosen JM, Huang S, Li Y. Dev Biol. 2010;346:196–203.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Forsbach G, Güitrón-Cantú A, Vázquez-Lara J, Mota-Morales M, Díaz-Mendoza ML. Virilizing adrenal adenoma and primary amenorrhea in a girl with adrenal hyperplasia. Arch Gynecol Obstet. 2000;263:134–6.

    Article  CAS  PubMed  Google Scholar 

  74. Hickey TE, Robinson JLL, Carroll JS, Tilley WD. Minireview: the androgen receptor in breast tissues: growth inhibitor, tumor suppressor, oncogene? Mol Endocrinol (Baltimore, Md). 2012;26:1252–67.

    Article  CAS  Google Scholar 

  75. Peters AA, Ingman WV, Tilley WD, Butler LM. Differential effects of exogenous androgen and an androgen receptor antagonist in the peri- and postpubertal murine mammary gland. Endocrinology. 2011;152:3728–37.

    Article  CAS  PubMed  Google Scholar 

  76. Zhou J, Ng S, Adesanya-Famuiya O, Anderson K, Bondy CA. Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression. FASEB J Off Publ Fed Am Soc Exp Biol. 2000;14:1725–30.

    CAS  Google Scholar 

  77. Gao YRE, Walters KA, Desai R, Zhou H, Handelsman DJ, Simanainen U. Androgen receptor inactivation resulted in acceleration in pubertal mammary gland growth, upregulation of ERα expression, and Wnt/β-catenin signaling in female mice. Endocrinology. 2014;155:4951–63.

    Article  PubMed  CAS  Google Scholar 

  78. Yeh S. Abnormal mammary gland development and growth retardation in female mice and MCF7 breast cancer cells lacking androgen receptor. J Exp Med. 2003;198:1899–908.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Eigeliene N, Elo T, Linhala M, Hurme S, Erkkola R, Harkonen P. Androgens inhibit the stimulatory action of 17-estradiol on normal human breast tissue in explant cultures. J Clin Endocrinol Metab. 2012;97:E1116–27.

    Article  CAS  PubMed  Google Scholar 

  80. Need EF, Selth LA, Harris TJ, Birrell SN, Tilley WD, Buchanan G. Research resource: interplay between the genomic and transcriptional networks of androgen receptor and estrogen receptor alpha in luminal breast cancer cells. Mol Endocrinol. 2012;26:1941–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Peters AA, Buchanan G, Ricciardelli C, Bianco-Miotto T, Centenera MM, Harris JM, et al. Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer. Cancer Res. 2009;69:6131–40.

    Article  CAS  PubMed  Google Scholar 

  82. Chakravarty D, Tekmal RR, Vadlamudi RK. PELP1: a novel therapeutic target for hormonal cancers. IUBMB Life. 2010;62:162–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  83. Girard BJ, Daniel AR, Lange CA, Ostrander JH. PELP1: a review of PELP1 interactions, signaling, and biology. Mol Cell Endocrinol. 2014;382:642–51.

    Article  CAS  PubMed  Google Scholar 

  84. Lanzino M, Maris P, Sirianni R, Barone I, Casaburi I, Chimento A, et al. DAX-1, as an androgen-target gene, inhibits aromatase expression: a novel mechanism blocking estrogen- dependent breast cancer cell proliferation. Cell Death Dis. 2013;4:e724.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Wong MM, Guo C, Zhang J. Nuclear receptor corepressor complexes in cancer: mechanism, function and regulation. Am J Clin Exp Urol. 2014;2:169–87.

    PubMed Central  PubMed  Google Scholar 

  86. Wang X, Yarid N, McMahon L, Yang Q, Hicks DG. Expression of androgen receptor and its association with estrogen receptor and androgen receptor downstream proteins in normal/benign breast luminal epithelium. Appl Immunohistochem Mol Morphol. 2014;22:498–504.

    Article  CAS  PubMed  Google Scholar 

  87. Tarulli GA, Butler LM, Tilley WD, Hickey TE. Bringing androgens up a NOTCH in breast cancer. Endocr Relat Cancer. 2014;21:T183–202.

    Article  CAS  PubMed  Google Scholar 

  88. Ramakrishnan R, Khan SA, Badve S. Morphological changes in breast tissue with menstrual cycle. Mod Pathol. 2002;15:1348–56.

    Article  PubMed  Google Scholar 

  89. Ferguson DJ, Anderson TJ. Morphological evaluation of cell turnover in relation to the menstrual cycle in the “resting” human breast. Br J Cancer. 1981;44:177–81.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Vogel PM, Georgiade NG, Fetter BF, Vogel FS, McCarty KS. The correlation of histologic changes in the human breast with the menstrual cycle. Am J Pathol. 1981;104:23–34.

    PubMed Central  CAS  PubMed  Google Scholar 

  91. Thomson AA, Marker PC. Branching morphogenesis in the prostate gland and seminal vesicles. Differentiation. 2006;74:382–92.

    Article  CAS  PubMed  Google Scholar 

  92. Crane JL, Cao X. Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling. J Clin Invest. 2014;124:466–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Hameedaldeen A, Liu J, Batres A, Graves G, Graves D. FOXO1, TGF-β regulation and wound healing. IJMS. 2014;15:16257–69.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  94. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000;14:163–76.

    PubMed Central  PubMed  Google Scholar 

  95. Jenkins G. The role of proteases in transforming growth factor-β activation. Int J Biochem Cell Biol. 2008;40:1068–78.

    Article  CAS  PubMed  Google Scholar 

  96. Wipff P, Hinz B. Integrins and the activation of latent transforming growth factor β1—an intimate relationship. Eur J Cell Biol. 2008;87:601–15.

    Article  CAS  PubMed  Google Scholar 

  97. Moses H, Barcellos-Hoff MH. TGF-biology in mammary development and breast cancer. Cold Spring Harb Perspect Biol. 2011;3:a003277.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  98. Barcellos-Hoff M, Akhurst RJ. Transforming growth factor-β in breast cancer: too much, too late. Breast Cancer Res. 2009;11:202.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  99. Wrana JL. Signaling by the TGF-beta superfamily. Cold Spring Harb Perspect Biol. 2013;5:a011197.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  100. Silberstein GB, Daniel CW. Reversible inhibition of mammary gland growth by transforming growth factor-beta. Science. 1987;237:291–3.

    Article  CAS  PubMed  Google Scholar 

  101. Zugmaier G, Lippman ME. Effects of TGF beta on normal and malignant mammary epithelium. Ann N Y Acad Sci. 1990;593:272–5.

    Article  CAS  PubMed  Google Scholar 

  102. Pierce DF, Johnson MD, Matsui Y, Robinson SD, Gold LI, Purchio AF, et al. Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-beta 1. Genes Dev. 1993;7:2308–17.

    Article  CAS  PubMed  Google Scholar 

  103. Roarty K, Baxley SE, Crowley MR, Frost AR, Serra R. Loss of TGF-β or Wnt5a results in an increase in Wnt/β-catenin activity and redirects mammary tumour phenotype. Breast Cancer Res. 2009;11:R19.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  104. Roarty K, Serra R. Wnt5a is required for proper mammary gland development and TGF-mediated inhibition of ductal growth. Development. 2007;134:3929–39.

    Article  CAS  PubMed  Google Scholar 

  105. Lazarus KA, Brown KA, Young MJ, Zhao Z, Coulson RS, Chand AL, et al. Conditional overexpression of liver receptor homolog-1 in female mouse mammary epithelium results in altered mammary morphogenesis via the induction of TGF-β. Endocrinology. 2014;155:1606–17.

    Article  PubMed  CAS  Google Scholar 

  106. Chand AL, Wijayakumara DD, Knower KC, Herridge KA, Howard TL, Lazarus KA, et al. The orphan nuclear receptor LRH-1 and ERα activate GREB1 expression to induce breast cancer cell proliferation. PLoS ONE. 2012;7:e31593.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Mohammed H, D’Santos C, Serandour AA, Ali HR, Brown GD, Atkins A, et al. Endogenous purification reveals GREB1as a key estrogen receptor regulatory factor. Cell Rep. 2013;3:342–9.

    Article  CAS  PubMed  Google Scholar 

  108. Itman C, Wong C, Hunyadi B, Ernst M, Jans DA, Loveland KL. Smad3 dosage determines androgen responsiveness and sets the pace of postnatal testis development. Endocrinology. 2011;152:2076–89.

    Article  CAS  PubMed  Google Scholar 

  109. Justulin Jr LA, Della-Coleta HHM, Taboga SR, Felisbino SL. Matrix metalloproteinase (MMP)-2 and MMP-9 activity and localization during ventral prostate atrophy and regrowth. Int J Androl. 2010;33:696–708.

    Article  CAS  PubMed  Google Scholar 

  110. Cocolakis E, Dai M, Drevet L, Ho J, Haines E, Ali S, et al. Smad signaling antagonizes STAT5-mediated gene transcription and mammary epithelial cell differentiation. J Biol Chem. 2007;283:1293–307.

    Article  PubMed  CAS  Google Scholar 

  111. Chuang LSH, Ito K, Ito Y. RUNX family: regulation and diversification of roles through interacting proteins. Int J Cancer. 2012;132:1260–71.

    Article  PubMed  CAS  Google Scholar 

  112. Chang TH-T, Kunasegaran K, Tarulli GA, De Silva D, Voorhoeve PM, Pietersen AM. New insights into lineage restriction of mammary gland epithelium using parity-identified mammary epithelial cells. Breast Cancer Res. 2014;16:R1.

    Article  PubMed Central  PubMed  Google Scholar 

  113. Jhappan C, Geiser AG, Kordon EC, Bagheri D, Hennighausen L, Roberts AB, et al. Targeting expression of a transforming growth factor beta 1 transgene to the pregnant mammary gland inhibits alveolar development and lactation. EMBO J. 1993;12:1835–45.

    PubMed Central  CAS  PubMed  Google Scholar 

  114. Kordon EC, McKnight RA, Jhappan C, Hennighausen L, Merlino G, Smith GH. Ectopic TGF beta 1 expression in the secretory mammary epithelium induces early senescence of the epithelial stem cell population. Dev Biol. 1995;168:47–61.

    Article  CAS  PubMed  Google Scholar 

  115. Boulanger CA, Wagner K-U, Smith GH. Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-β1 expression. Oncogene. 2004;24:552–60.

    Article  CAS  Google Scholar 

  116. Booth BW, Jhappan C, Merlino G, Smith GH. TGFβ1 and TGFα contrarily affect alveolar survival and tumorigenesis in mouse mammary epithelium. Int J Cancer. 2006;120:493–9.

    Article  CAS  Google Scholar 

  117. Muraoka-Cook RS, Kurokawa H, Koh Y, Forbes JT, Roebuck LR, Barcellos-Hoff MH, et al. Conditional overexpression of active transforming growth factor beta1 in vivo accelerates metastases of transgenic mammary tumors. Cancer Res. 2004;64:9002–11.

    Article  CAS  PubMed  Google Scholar 

  118. Muraoka RS, Koh Y, Roebuck LR, Sanders ME, Brantley-Sieders D, Gorska AE, et al. Increased malignancy of Neu-induced mammary tumors overexpressing active transforming growth factor 1. Mol Cell Biol. 2003;23:8691–703.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  119. Asselin-Labat M-L, Sutherland KD, Barker H, Thomas R, Shackleton M, Forrest NC, et al. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol. 2006;9:201–9.

    Article  PubMed  CAS  Google Scholar 

  120. Kouros-Mehr H, Slorach EM, Sternlicht MD, Werb Z. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell. 2006;127:1041–55.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. Kouros-Mehr H, Kim J-W, Bechis SK, Werb Z. GATA-3 and the regulation of the mammary luminal cell fate. Curr Opin Cell Biol. 2008;20:164–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  122. Hurtado A, Holmes KA, Ross-Innes CS, Schmidt D, Carroll JS. Hurtado 2011-NatGen. Nat Genet. 2010;43:27–33.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  123. Theodorou V, Stark R, Menon S, Carroll JS. GATA3 acts upstream of FOXA1 in mediating ESR1 binding by shaping enhancer accessibility. Genome Res. 2013;23:12–22.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  124. Bernardo GM, Keri RA. FOXA1: a transcription factor with parallel functions in development and cancer. Biosci Rep. 2011;32:113–30.

    Article  CAS  Google Scholar 

  125. Xu J, Liao L, Ning G, Yoshida-Komiya H, Deng C, O’Malley BW. The steroid receptor coactivator SRC-3 (p/CIP/RAC3/AIB1/ACTR/TRAM-1) is required for normal growth, puberty, female reproductive function, and mammary gland development. Proc Natl Acad Sci U S A. 2000;97:6379–84.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  126. Bernardo GM, Lozada KL, Miedler JD, Harburg G, Hewitt SC, Mosley JD, et al. FOXA1 is an essential determinant of ER-alpha expression and mammary ductal morphogenesis. Development. 2010;137:2045–54.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  127. Robinson JLL, Carroll JS. FoxA1 is a key mediator of hormonal response in breast and prostate cancer. Front Endocrinol (Lausanne). 2012;3:68.

    CAS  Google Scholar 

  128. Andres SA, Wittliff JL. Co-expression of genes with estrogen receptor-α and progesterone receptor in human breast carcinoma tissue. Horm Mol Biol Clin Investig. 2012;12:377–90.

    CAS  PubMed  Google Scholar 

  129. Kong SL, Li G, Loh SL, Sung W-K, Liu ET. Cellular reprogramming by the conjoint action of ERa, FOXA1, and GATA3 to a ligand-inducible growth state. Mol Syst Biol. 2011;7:1–14.

    Google Scholar 

  130. Manavathi B. Estrogen receptor coregulators and pioneer factors: the orchestrators of mammary gland cell fate and development. Front Cell Dev Biol. 2014;2:1–13.

    Article  Google Scholar 

  131. Oakes SR, Naylor MJ, Asselin-Labat ML, Blazek KD, Gardiner-Garden M, Hilton HN, et al. The Ets transcription factor Elf5 specifies mammary alveolar cell fate. Genes Dev. 2008;22:581–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  132. Choi YS, Chakrabarti R, Escamilla-Hernandez R, Sinha S. Dev Biol. 2009;329:227–41.

    Article  CAS  PubMed  Google Scholar 

  133. Lee HJ, Gallego-Ortega D, Ledger A, Schramek D, Joshi P, Szwarc MM, et al. Progesterone drives mammary secretory differentiation via RankL-mediated induction of Elf5 in luminal progenitor cells. Development. 2013;140:1397–401.

    Article  CAS  PubMed  Google Scholar 

  134. Visvader JE, Stingl J. Mammary stem cells and the differentiation hierarchy: current status and perspectives. Genes Dev. 2014;28:1143–58.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  135. Lim E, Wu D, Pal B, Bouras T, Asselin-Labat M-L, Vaillant F, et al. Transcriptome analyses of mouse and human mammary cell subpopulations reveal multiple conserved genes and pathways. Breast Cancer Res. 2010;12:R21.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  137. Chakrabarti R, Wei Y, Romano R-A, DeCoste C, Kang Y, Sinha S. Elf5 regulates mammary gland stem/progenitor cell fate by influencing notch signaling. Stem Cells. 2012;30:1496–508.

    Article  CAS  PubMed  Google Scholar 

  138. Kalyuga M, Gallego-Ortega D, Lee HJ, Roden DL, Cowley MJ, Caldon CE, et al. ELF5 suppresses estrogen sensitivity and underpins the acquisition of antiestrogen resistance in luminal breast cancer. PLoS Biol. 2012;10:e1001461.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  139. Sebastian T, Johnson PF. Stop and go: anti-proliferative and mitogenic functions of the transcription factor C/EBPbeta. Cell Cycle. 2006;5:953–7.

    Article  CAS  PubMed  Google Scholar 

  140. Seagroves TN, Krnacik S, Raught B, Gay J, Burgess-Beusse B, Darlington GJ, et al. C/EBPbeta, but not C/EBPalpha, is essential for ductal morphogenesis, lobuloalveolar proliferation, and functional differentiation in the mouse mammary gland. Genes Dev. 1998;12:1917–28.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  141. Grimm SL, Contreras A, Barcellos-Hoff MH, Rosen JM. Cell cycle defects contribute to a block in hormone-induced mammary gland proliferation in CCAAT/enhancer-binding protein (C/EBPbeta)-null mice. J Biol Chem. 2005;280:36301–9.

    Article  CAS  PubMed  Google Scholar 

  142. Liu Q, Boudot A, Ni J, Hennessey T, Beauparlant SL, Rajabi HN, et al. Cyclin D1 and C/EBP LAP1 operate in a common pathway to promote mammary epithelial cell differentiation. Mol Cell Biol. 2014;34:3168–79.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  143. Frech MS, Torre KM, Robinson GW, Furth PA. Loss of cyclin D1 in concert with deregulated estrogen receptor α expression induces DNA damage response activation and interrupts mammary gland morphogenesis. Oncogene. 2007;27:3186–93.

    Article  PubMed  CAS  Google Scholar 

  144. Grimm SL, Rosen JM. The role of C/EBPbeta in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia. 2003;8:191–204.

    Article  PubMed  Google Scholar 

  145. Liang X-H, Zhao Z-A, Deng W-B, Tian Z, Lei W, Xu X, et al. Estrogen regulates amiloride-binding protein 1 through CCAAT/enhancer-binding protein-β in mouse uterus during embryo implantation and decidualization. Endocrinology. 2010;151:5007–16.

    Article  CAS  PubMed  Google Scholar 

  146. Wang W, Li Q, Bagchi IC, Bagchi MK. The CCAAT/enhancer binding protein β is a critical regulator of steroid-induced mitotic expansion of uterine stromal cells during decidualization. Endocrinology. 2010;151:3929–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  147. Ramathal C, Bagchi IC, Bagchi MK. Lack of CCAAT enhancer binding protein beta in uterine epithelial cells impairs estrogen-induced DNA replication, induces DNA damage response pathways, and promotes apoptosis. Mol Cell Biol. 2010;30:1607–19.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  148. Nerlov C. The C/EBP family of transcription factors: a paradigm for interaction between gene expression and proliferation control. Trends Cell Biol. 2007;17:318–24.

    Article  CAS  PubMed  Google Scholar 

  149. Grimm SL, Seagroves TN, Kabotyanski EB, Hovey RC, Vonderhaar BK, Lydon JP, et al. Disruption of steroid and prolactin receptor patterning in the mammary gland correlates with a block in lobuloalveolar development. Mol Endocrinol. 2002;16:2675–91.

    Article  CAS  PubMed  Google Scholar 

  150. Kang JH, Tsai-Morris CH, Dufau ML. Complex formation and interactions between transcription factors essential for human prolactin receptor gene transcription. Mol Cell Biol. 2011;31:3208–22.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  151. Goldhar AS, Duan R, Ginsburg E, Vonderhaar BK. Progesterone induces expression of the prolactin receptor gene through cooperative action of Sp1 and C/EBP. Mol Cell Endocrinol. 2011;335:148–57.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  152. Dong J, Tsai-Morris C-H, Dufau ML. A novel estradiol/estrogen receptor alpha-dependent transcriptional mechanism controls expression of the human prolactin receptor. J Biol Chem. 2006;281:18825–36.

    Article  CAS  PubMed  Google Scholar 

  153. Fujimori K, Amano F. Forkhead transcription factor Foxa1 is a novel target gene of C/EBPβ and suppresses the early phase of adipogenesis. Gene. 2011;473:150–6.

    Article  CAS  PubMed  Google Scholar 

  154. Sutinen P, Malinen M, Heikkinen S, Palvimo JJ. SUMOylation modulates the transcriptional activity of androgen receptor in a target gene and pathway selective manner. Nucleic Acids Res. 2014;42:8310–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  155. van Bragt MP, Hu X, Xie Y, Li Z. RUNX1, a transcription factor mutated in breast cancer, controls the fate of ER-positive mammary luminal cells. eLife. 2014;3:e03881.

    PubMed  Google Scholar 

  156. Kouros-Mehr H, Werb Z. Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev Dyn. 2006;235:3404–12.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  157. Owens TW, Rogers RL, Best SA, Ledger A, Mooney AM, Ferguson A, et al. Runx2 is a novel regulator of mammary epithelial cell fate in development and breast cancer. Cancer Res. 2014;74:5277–86.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  158. Chimge N-O, Baniwal SK, Little GH, Chen Y-B, Kahn M, Tripathy D, et al. Regulation of breast cancer metastasis by Runx2 and estrogen signaling: the role of SNAI2. Breast Cancer Res. 2011;13:R127.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  159. Huang B, Qu Z, Ong CW, Tsang Y-HN, Xiao G, Shapiro D, et al. RUNX3 acts as a tumor suppressor in breast cancer by targetingestrogen receptor a. Oncogene. 2011;31:527–34.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  160. Blyth K, Vaillant F, Jenkins A, McDonald L, Pringle MA, Huser C, et al. Runx2 in normal tissues and cancer cells: a developing story. Blood Cell Mol Dis. 2010;45:117–23.

    Article  CAS  Google Scholar 

  161. Wang L, Brugge JS, Janes KA. Intersection of FOXO- and RUNX1-mediated gene expression programs in single breast epithelial cells during morphogenesis and tumor progression. Proc Natl Acad Sci. 2011;108:E803–12.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  162. Wall EH, Case LK, Hewitt SC, Nguyen-Vu T, Candelaria NR, Teuscher C, et al. Genetic control of ductal morphology, estrogen-induced ductal growth, and gene expression in female mouse mammary gland. Endocrinology. 2014;155:3025–35.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  163. Douglas NC, Papaioannou VE. The T-box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia. 2013;18:143–7.

    Article  PubMed Central  PubMed  Google Scholar 

  164. 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:e111442.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  165. Chitilian JM, Thillainadesan G, Manias JL, Chang WY, Walker E, Isovic M, et al. Critical components of the pluripotency network are targets for the p300/CBP interacting protein (p/CIP) in embryonic stem cells. Stem Cells. 2014;32:204–15.

    Article  CAS  PubMed  Google Scholar 

  166. Fan W, Huang X, Chen C, Gray J, Huang T. TBX3 and its isoform TBX3+2a are functionally distinctive in inhibition of senescence and are overexpressed in a subset of breast cancer cell lines. Cancer Res. 2004;64:5132–9.

    Article  CAS  PubMed  Google Scholar 

  167. Fillmore CM, Gupta PB, Rudnick JA, Caballero S, Keller PJ, Lander ES, et al. Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling. Proc Natl Acad Sci. 2010;107:21737–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  168. Li J, Weinberg MS, Zerbini L, Prince S. The oncogenic TBX3 is a downstream target and mediator of the TGF- 1 signaling pathway. Mol Biol Cell. 2013;24:3569–76.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  169. Seksenyan A, Kadavallore A, Walts AE, de la Torre B, Berel D, Strom SP, et al. TOX3 is expressed in mammary ER+ epithelial cells and regulates ER target genes in luminal breast cancer. BMC Cancer. 2015;15:52.

    Article  CAS  Google Scholar 

  170. Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, et al. The landscape of cancer genes and mutational processes in breast cancer. Nature. 2012;486:400–4.

    PubMed Central  CAS  PubMed  Google Scholar 

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Funding Information

This work was supported by grants from the National Health and Medical Research Council of Australia (ID 1008349; ID 1084416) and Cancer Australia (ID 627229), the National Breast Cancer Foundation (ID PS-15-041), a Fellowship Award from the US Department of Defense Breast Cancer Research Program (BCRP; W81XWH-11-1-0592) and a Florey Fellowship from the Royal Adelaide Hospital Research Foundation.

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  1. Dame Roma Mitchell Cancer Research Laboratories (DRMCRL), School of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia

    Gerard A. Tarulli, Geraldine Laven-Law, Wayne D. Tilley & Theresa E. Hickey

  2. Breast Cancer Genetics Laboratory, Centre for Personalised Cancer Medicine, School of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia

    Reshma Shakya

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  1. Gerard A. Tarulli
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Tarulli, G.A., Laven-Law, G., Shakya, R. et al. Hormone-Sensing Mammary Epithelial Progenitors: Emerging Identity and Hormonal Regulation. J Mammary Gland Biol Neoplasia 20, 75–91 (2015). https://doi.org/10.1007/s10911-015-9344-1

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