Advertisement

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

  • Gerard A. Tarulli
  • Geraldine Laven-Law
  • Reshma Shakya
  • Wayne D. Tilley
  • Theresa E. Hickey
Article

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.

Keywords

Endocrine hormones Hormone-sensing cells Luminal progenitors Androgen Prolactin 

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

Notes

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.

References

  1. 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.PubMedCentralPubMedGoogle Scholar
  2. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 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.Google Scholar
  5. 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.PubMedGoogle Scholar
  6. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.CrossRefGoogle Scholar
  9. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 11.
    Lain AR, Creighton CJ, Conneely OM. Research resource: progesterone receptor targetome underlying mammary gland branching morphogenesis. Mol Endocrinol. 2013;27:1743–61.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.PubMedCentralPubMedGoogle Scholar
  15. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedGoogle Scholar
  20. 20.
    Russo J, Russo IH. Development of the human breast. Maturitas. 2004;49:2–15.PubMedCrossRefGoogle Scholar
  21. 21.
    Russo IH, Russo J. Role of hormones in mammary cancer initiation and progression. J Mammary Gland Biol Neoplasia. 1998;3:49–61.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Booth BW, Smith GH. Breast Cancer Res. 2006;8:R49.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 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.CrossRefGoogle Scholar
  38. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 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.CrossRefGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 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.PubMedCrossRefGoogle Scholar
  44. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. 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.PubMedGoogle Scholar
  47. 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.PubMedCrossRefGoogle Scholar
  48. 48.
    Chepko G, Smith GH. Three division-competent, structurally-distinct cell populations contribute to murine mammary epithelial renewal. Tissue Cell. 1997;29:239–53.PubMedCrossRefGoogle Scholar
  49. 49.
    Smith GH, Chepko G. Mammary epithelial stem cells. Microsc Res Tech. 2001;52:190–203.PubMedCrossRefGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 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.PubMedCrossRefGoogle Scholar
  53. 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.PubMedCrossRefGoogle Scholar
  54. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 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.PubMedCrossRefGoogle Scholar
  56. 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.PubMedCrossRefGoogle Scholar
  57. 57.
    Brisken C. Progesterone signalling in breast cancer: a neglected hormone coming into the limelight. Nat Rev Cancer. 2013;13:385–96.PubMedCrossRefGoogle Scholar
  58. 58.
    Tanos T, Rojo L, Echeverria P, Brisken C. ER and PR signaling nodes during mammary gland development. Breast Cancer Res. 2012;14:210.PubMedCentralPubMedCrossRefGoogle Scholar
  59. 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.PubMedCrossRefGoogle Scholar
  60. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  63. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 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.PubMedCrossRefGoogle Scholar
  65. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 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.PubMedCrossRefGoogle Scholar
  67. 67.
    Hovey RC. Local insulin-like growth factor-II mediates prolactin-induced mammary gland development. Mol Endocrinol. 2002;17:460–71.PubMedCrossRefGoogle Scholar
  68. 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.CrossRefGoogle Scholar
  69. 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.PubMedCrossRefGoogle Scholar
  70. 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.PubMedCrossRefGoogle Scholar
  71. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Dong J, Tong T, Reynado AM, Rosen JM, Huang S, Li Y. Dev Biol. 2010;346:196–203.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 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.PubMedCrossRefGoogle Scholar
  74. 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.CrossRefGoogle Scholar
  75. 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.PubMedCrossRefGoogle Scholar
  76. 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.Google Scholar
  77. 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.PubMedCrossRefGoogle Scholar
  78. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 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.PubMedCrossRefGoogle Scholar
  80. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  81. 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.PubMedCrossRefGoogle Scholar
  82. 82.
    Chakravarty D, Tekmal RR, Vadlamudi RK. PELP1: a novel therapeutic target for hormonal cancers. IUBMB Life. 2010;62:162–9.PubMedCentralPubMedCrossRefGoogle Scholar
  83. 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.PubMedCrossRefGoogle Scholar
  84. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  85. 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.PubMedCentralPubMedGoogle Scholar
  86. 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.PubMedCrossRefGoogle Scholar
  87. 87.
    Tarulli GA, Butler LM, Tilley WD, Hickey TE. Bringing androgens up a NOTCH in breast cancer. Endocr Relat Cancer. 2014;21:T183–202.PubMedCrossRefGoogle Scholar
  88. 88.
    Ramakrishnan R, Khan SA, Badve S. Morphological changes in breast tissue with menstrual cycle. Mod Pathol. 2002;15:1348–56.PubMedCrossRefGoogle Scholar
  89. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 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.PubMedCentralPubMedGoogle Scholar
  91. 91.
    Thomson AA, Marker PC. Branching morphogenesis in the prostate gland and seminal vesicles. Differentiation. 2006;74:382–92.PubMedCrossRefGoogle Scholar
  92. 92.
    Crane JL, Cao X. Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling. J Clin Invest. 2014;124:466–72.PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Hameedaldeen A, Liu J, Batres A, Graves G, Graves D. FOXO1, TGF-β regulation and wound healing. IJMS. 2014;15:16257–69.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 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.PubMedCentralPubMedGoogle Scholar
  95. 95.
    Jenkins G. The role of proteases in transforming growth factor-β activation. Int J Biochem Cell Biol. 2008;40:1068–78.PubMedCrossRefGoogle Scholar
  96. 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.PubMedCrossRefGoogle Scholar
  97. 97.
    Moses H, Barcellos-Hoff MH. TGF-biology in mammary development and breast cancer. Cold Spring Harb Perspect Biol. 2011;3:a003277.PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    Barcellos-Hoff M, Akhurst RJ. Transforming growth factor-β in breast cancer: too much, too late. Breast Cancer Res. 2009;11:202.PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Wrana JL. Signaling by the TGF-beta superfamily. Cold Spring Harb Perspect Biol. 2013;5:a011197.PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Silberstein GB, Daniel CW. Reversible inhibition of mammary gland growth by transforming growth factor-beta. Science. 1987;237:291–3.PubMedCrossRefGoogle Scholar
  101. 101.
    Zugmaier G, Lippman ME. Effects of TGF beta on normal and malignant mammary epithelium. Ann N Y Acad Sci. 1990;593:272–5.PubMedCrossRefGoogle Scholar
  102. 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.PubMedCrossRefGoogle Scholar
  103. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  104. 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.PubMedCrossRefGoogle Scholar
  105. 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.PubMedCrossRefGoogle Scholar
  106. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  107. 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.PubMedCrossRefGoogle Scholar
  108. 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.PubMedCrossRefGoogle Scholar
  109. 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.PubMedCrossRefGoogle Scholar
  110. 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.PubMedCrossRefGoogle Scholar
  111. 111.
    Chuang LSH, Ito K, Ito Y. RUNX family: regulation and diversification of roles through interacting proteins. Int J Cancer. 2012;132:1260–71.PubMedCrossRefGoogle Scholar
  112. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  113. 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.PubMedCentralPubMedGoogle Scholar
  114. 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.PubMedCrossRefGoogle Scholar
  115. 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.CrossRefGoogle Scholar
  116. 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.CrossRefGoogle Scholar
  117. 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.PubMedCrossRefGoogle Scholar
  118. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  119. 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.PubMedCrossRefGoogle Scholar
  120. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  121. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  122. 122.
    Hurtado A, Holmes KA, Ross-Innes CS, Schmidt D, Carroll JS. Hurtado 2011-NatGen. Nat Genet. 2010;43:27–33.PubMedCentralPubMedCrossRefGoogle Scholar
  123. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Bernardo GM, Keri RA. FOXA1: a transcription factor with parallel functions in development and cancer. Biosci Rep. 2011;32:113–30.CrossRefGoogle Scholar
  125. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  126. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  127. 127.
    Robinson JLL, Carroll JS. FoxA1 is a key mediator of hormonal response in breast and prostate cancer. Front Endocrinol (Lausanne). 2012;3:68.Google Scholar
  128. 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.PubMedGoogle Scholar
  129. 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. 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.CrossRefGoogle Scholar
  131. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  132. 132.
    Choi YS, Chakrabarti R, Escamilla-Hernandez R, Sinha S. Dev Biol. 2009;329:227–41.PubMedCrossRefGoogle Scholar
  133. 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.PubMedCrossRefGoogle Scholar
  134. 134.
    Visvader JE, Stingl J. Mammary stem cells and the differentiation hierarchy: current status and perspectives. Genes Dev. 2014;28:1143–58.PubMedCentralPubMedCrossRefGoogle Scholar
  135. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  136. 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.PubMedCrossRefGoogle Scholar
  137. 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.PubMedCrossRefGoogle Scholar
  138. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  139. 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.PubMedCrossRefGoogle Scholar
  140. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  141. 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.PubMedCrossRefGoogle Scholar
  142. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  143. 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.PubMedCrossRefGoogle Scholar
  144. 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.PubMedCrossRefGoogle Scholar
  145. 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.PubMedCrossRefGoogle Scholar
  146. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  147. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  148. 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.PubMedCrossRefGoogle Scholar
  149. 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.PubMedCrossRefGoogle Scholar
  150. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  151. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  152. 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.PubMedCrossRefGoogle Scholar
  153. 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.PubMedCrossRefGoogle Scholar
  154. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  155. 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.PubMedGoogle Scholar
  156. 156.
    Kouros-Mehr H, Werb Z. Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev Dyn. 2006;235:3404–12.PubMedCentralPubMedCrossRefGoogle Scholar
  157. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  158. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  159. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  160. 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.CrossRefGoogle Scholar
  161. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  162. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  163. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  164. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  165. 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.PubMedCrossRefGoogle Scholar
  166. 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.PubMedCrossRefGoogle Scholar
  167. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  168. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  169. 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.CrossRefGoogle Scholar
  170. 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.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Gerard A. Tarulli
    • 1
  • Geraldine Laven-Law
    • 1
  • Reshma Shakya
    • 2
  • Wayne D. Tilley
    • 1
  • Theresa E. Hickey
    • 1
  1. 1.Dame Roma Mitchell Cancer Research Laboratories (DRMCRL), School of Medicine, Faculty of Health SciencesThe University of AdelaideAdelaideAustralia
  2. 2.Breast Cancer Genetics Laboratory, Centre for Personalised Cancer Medicine, School of Medicine, Faculty of Health SciencesThe University of AdelaideAdelaideAustralia

Personalised recommendations