Skip to main content

Advertisement

Springer Nature Link
Log in

Steroid Hormones, Steroid Receptors, and Breast Cancer Stem Cells

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

Abstract

The ovarian hormones progesterone and estrogen play important roles in breast cancer etiology, proliferation, and treatment. Androgens may also contribute to breast cancer risk and progression. In recent years, significant advances have been made in defining the roles of these steroid hormones in stem cell homeostasis in the breast. Stem cells are potential origins of breast cancer and may dictate tumor phenotype. At least a portion of breast cancers are proposed to be driven by cancer stem cells (CSCs), cells that mimic the self-renewing and repopulating properties of normal stem cells, and can confer drug resistance. Progesterone has been identified as the critical hormone regulating normal murine mammary stem cell (MaSC) populations and normal human breast stem cells. Synthetic progestins increase human breast cancer risk; one theory speculates that this occurs through increased stem cells. Progesterone treatment also increases breast CSCs in established breast cancer cell lines. This is mediated in part through progesterone regulation of transcription factors, signal transduction pathways, and microRNAs. There is also emerging evidence that estrogens and androgens can regulate breast CSC numbers. The evolving concept that a breast CSC phenotype is dynamic and can be influenced by cell signaling and external cues emphasizes that steroid hormones could be crucial players in controlling CSC number and function. Here we review recent studies on steroid hormone regulation of breast CSCs, and discuss mechanisms by which this occurs.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

Notes

  1. B.M. Jacobsen, personal communication

  2. J. Finlay-Schultz and C.A. Sartorius, unpublished data

  3. J. Finlay-Schultz and C.A. Sartorius, unpublished data

Abbreviations

AR:

Androgen receptor

ALDH:

Aldehyde dehydrogenase

CK5:

Cytokeratin 5

CSC:

Cancer stem cell

DHT:

Dihydrotestosterone

DMBA:

7,12-dimethylbenz(a)anthracene

EGFR:

Epidermal growth factor receptor

ER:

Estrogen receptor (alpha)

FACS:

Fluorescent activated cell sorting

FGF:

Fibroblast growth factor

HRT:

Hormone replacement therapy

MaSC:

Mammary stem cell

MMTV:

Mouse mammary tumor virus

MPA:

Medroxyprogesterone acetate

MUC1:

Mucin 1

PR:

Progesterone receptor

PRKO:

Progesterone receptor knockout

RANK:

Receptor activator of nuclear factor kappa-B

RANKL:

receptor activator of nuclear factor kappa-B ligand

TNBC:

triple negative breast cancer

References

  1. Beatson G. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet. 1896;148(3803):162–5. doi:10.1016/S0140-6736(01)72384-7.

    Article  Google Scholar 

  2. Boyd S. On oophorectomy in the treatment of cancer. Br Med J. 1897;2(1918):890–6. doi:10.1136/bmj.2.1918.890.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Jordan VC. Tamoxifen as the first targeted long-term adjuvant therapy for breast cancer. Endocrinol Relat Cancer. 2014;21(3):R235–46. doi:10.1530/erc-14-0092.

    Article  CAS  Google Scholar 

  4. 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 

  5. Schedin P. Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer. 2006;6(4):281–91. doi:10.1038/nrc1839.

    Article  CAS  PubMed  Google Scholar 

  6. Bernstein L. Epidemiology of endocrine-related risk factors for breast cancer. J Mammary Gland Biol Neoplasia. 2002;7(1):3–15. doi:10.1023/A:1015714305420.

    Article  PubMed  Google Scholar 

  7. Hankinson SE, Colditz GA, Willett WC. Towards an integrated model for breast cancer etiology: the lifelong interplay of genes, lifestyle, and hormones. Breast Cancer Res. 2004;6(5):213–8. doi:10.1186/bcr921.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Gierisch JM, Coeytaux RR, Urrutia RP, Havrilesky LJ, Moorman PG, Lowery WJ, et al. Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review. Cancer Epidemiol Biomarkers Prev. 2013;22(11):1931–43. doi:10.1158/1055-9965.epi-13-0298.

    Article  PubMed  Google Scholar 

  9. Suzuki R, Orsini N, Saji S, Key TJ, Wolk A. Body weight and incidence of breast cancer defined by estrogen and progesterone receptor status--a meta-analysis. Int J Cancer. 2009;124(3):698–712. doi:10.1002/ijc.23943.

    Article  CAS  PubMed  Google Scholar 

  10. 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(7299):803–7. doi:10.1038/nature09091.

    Article  CAS  PubMed  Google Scholar 

  11. 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. doi:10.1038/nature09027.

    Article  CAS  PubMed  Google Scholar 

  12. 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. doi:10.1210/en.2008-1630.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11. doi:10.1038/35102167.

    Article  CAS  PubMed  Google Scholar 

  14. Elliott A, Adams J, Al-Hajj M. The ABCs of cancer stem cell drug resistance. IDrugs. 2010;13(9):632–5.

    CAS  PubMed  Google Scholar 

  15. Moore N, Lyle S. Quiescent, slow-cycling stem cell populations in cancer: a review of the evidence and discussion of significance. J Oncol. 2011;2011. doi:10.1155/2011/396076.

  16. Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 2009;458(7239):780–3. doi:10.1038/nature07733.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Kabos P, Haughian JM, Wang X, Dye WW, 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. doi:10.1007/s10549-010-1078-6.

    Article  CAS  PubMed  Google Scholar 

  18. Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A. 2009;106(33):13820–5. doi:10.1073/pnas.0905718106.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Fillmore CM, Kuperwasser C. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res. 2008;10(2):R25. doi:10.1186/bcr1982.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  20. Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci U S A. 2011;108(19):7950–5. doi:10.1073/pnas.1102454108.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Iliopoulos D, Hirsch HA, Wang G, Struhl K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci U S A. 2011;108(4):1397–402. doi:10.1073/pnas.1018898108.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Li Y, Laterra J. Cancer stem cells: distinct entities or dynamically regulated phenotypes? Cancer Res. 2012;72(3):576–80. doi:10.1158/0008-5472.can-11-3070.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Magee JA, Piskounova E, Morrison SJ. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell. 2012;21(3):283–96. doi:10.1016/j.ccr.2012.03.003.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Nguyen LV, Vanner R, Dirks P, Eaves CJ. Cancer stem cells: an evolving concept. Nat Rev Cancer. 2012;12(2):133–43. doi:10.1038/nrc3184.

    CAS  PubMed  Google Scholar 

  25. 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. doi:10.1073/pnas.0530291100.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Charafe-Jauffret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P, et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res. 2009;69(4):1302–13. doi:10.1158/0008-5472.CAN-08-2741.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Honeth G, Bendahl PO, Ringner M, Saal LH, Gruvberger-Saal SK, Lovgren K, et al. The CD44+/CD24- phenotype is enriched in basal-like breast tumors. Breast Cancer Res. 2008;10(3):R53. doi:10.1186/bcr2108.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  28. 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. doi:10.1016/j.ccr.2007.01.013.

    Article  CAS  PubMed  Google Scholar 

  29. 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. doi:10.1016/j.stem.2007.08.014.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Morimoto K, Kim SJ, Tanei T, Shimazu K, Tanji Y, Taguchi T, et al. Stem cell marker aldehyde dehydrogenase 1-positive breast cancers are characterized by negative estrogen receptor, positive human epidermal growth factor receptor type 2, and high Ki67 expression. Cancer Sci. 2009;100(6):1062–8. doi:10.1111/j.1349-7006.2009.01151.x.

    Article  CAS  PubMed  Google Scholar 

  31. Liu S, Cong Y, Wang D, Sun Y, Deng L, Liu Y, et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep. 2014;2(1):78–91. doi:10.1016/j.stemcr.2013.11.009.

    Article  CAS  Google Scholar 

  32. Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med. 2009;15(8):907–13. doi:10.1038/nm.2000.

    Article  CAS  PubMed  Google Scholar 

  33. Bocker W, Moll R, Poremba C, Holland R, Van Diest PJ, Dervan P, et al. Common adult stem cells in the human breast give rise to glandular and myoepithelial cell lineages: a new cell biological concept. Lab Invest. 2002;82(6):737–46. doi:10.1097/01.LAB.0000017371.72714.C5.

    Article  PubMed  Google Scholar 

  34. Boecker W, Buerger H. Evidence of progenitor cells of glandular and myoepithelial cell lineages in the human adult female breast epithelium: a new progenitor (adult stem) cell concept. Cell Prolif. 2003;36 Suppl 1:73–84. doi:10.1046/j.1365-2184.36.s.1.7.x.

    Article  PubMed  Google Scholar 

  35. Villadsen R, Fridriksdottir AJ, Ronnov-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. doi:10.1083/jcb.200611114.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. 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. doi:10.1158/0008-5472.can-05-0505.

    Article  CAS  PubMed  Google Scholar 

  37. 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. doi:10.1073/pnas.0706216105.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Axlund SD, Yoo BH, Rosen RB, Schaack J, Kabos P, Labarbera DV, et al. Progesterone-inducible cytokeratin 5-positive cells in luminal breast cancer exhibit progenitor properties. Horm Cancer. 2013;4(1):36–49. doi:10.1007/s12672-012-0127-5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Horwitz KB, McGuire WL. Specific progesterone receptors in human breast cancer. Steroids. 1975;25(4):497–505. doi:10.1016/0039-128X(75)90027-6.

    Article  CAS  PubMed  Google Scholar 

  40. Cui X, Schiff R, Arpino G, Osborne CK, Lee AV. Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy. J Clin Oncol. 2005;23(30):7721–35. doi:10.1200/jco.2005.09.004.

    Article  CAS  PubMed  Google Scholar 

  41. Knutson TP, Lange CA. Tracking progesterone receptor-mediated actions in breast cancer. Pharmacol Ther. 2013;142(1):114–25. doi:10.1016/j.pharmthera.2013.11.010.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  42. Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, et al. Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J. 1990;9(5):1603–14.

    PubMed Central  CAS  PubMed  Google Scholar 

  43. Mote PA, Bartow S, Tran N, Clarke CL. Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis. Breast Cancer Res Treat. 2002;72(2):163–72. doi:10.1023/A:1014820500738.

    Article  CAS  PubMed  Google Scholar 

  44. Graham JD, Yeates C, Balleine RL, Harvey SS, Milliken JS, Bilous AM, et al. Characterization of progesterone receptor A and B expression in human breast cancer. Cancer Res. 1995;55(21):5063–8.

    CAS  PubMed  Google Scholar 

  45. 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. doi:10.1093/jnci/djq527.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, Kuller LH, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010;304(15):1684–92. doi:10.1001/jama.2010.1500.

    Article  CAS  PubMed  Google Scholar 

  47. 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(4):R62. doi:10.1186/bcr3456.

    Article  PubMed Central  PubMed  Google Scholar 

  48. Narod SA. Hormone replacement therapy and the risk of breast cancer. Nat Rev Clin Oncol. 2011;8(11):669–76. doi:10.1038/nrclinonc.2011.110.

    Article  CAS  PubMed  Google Scholar 

  49. 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. doi:10.1210/jc.2008-0938.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Huggins C, Moon RC, Morii S. Extinction of experimental mammary cancer. I. Estradiol-17beta and progesterone. Proc Natl Acad Sci U S A. 1962;48:379–86. doi:10.1073/pnas.48.3.379.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. 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 

  52. Santen RJ, Song Y, Yue W, Wang JP, Heitjan DF. Effects of menopausal hormonal therapy on occult breast tumors. J Steroid Biochem Mol Biol. 2013;137:150–6. doi:10.1016/j.jsbmb.2013.05.008.

    Article  CAS  PubMed  Google Scholar 

  53. 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. doi:10.1038/onc.2012.275.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. 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. doi:10.1038/onc.2014.298.

    PubMed  PubMed Central  Google Scholar 

  55. 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. doi:10.1007/s10549-013-2817-2.

    PubMed Central  Google Scholar 

  56. 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. doi:10.1371/journal.pone.0077124.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Jambal P, Badtke MM, Harrell JC, Borges VF, Post MD, Sollender GE, et al. Estrogen switches pure mucinous breast cancer to invasive lobular carcinoma with mucinous features. Breast Cancer Res Treat. 2013;137(2):431–48. doi:10.1007/s10549-012-2377-x.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Kabos P, Finlay-Schultz J, Li C, Kline E, Finlayson C, Wisell J, et al. Patient-derived luminal breast cancer xenografts retain hormone receptor heterogeneity and help define unique estrogen-dependent gene signatures. Breast Cancer Res Treat. 2012;135(2):415–32. doi:10.1007/s10549-012-2164-8.

    Article  CAS  PubMed  Google Scholar 

  59. Yoo BH, Axlund SD, Kabos P, Reid BG, Schaack J, Sartorius CA, et al. A high-content assay to identify small-molecule modulators of a cancer stem cell population in luminal breast cancer. J Biomol Screen. 2012;17(9):1211–20. doi:10.1177/1087057112452138.

    Article  PubMed Central  PubMed  Google Scholar 

  60. Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008;107(1):103–11. doi:10.1007/s10549-007-9523-x.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Ghatge RP, Jacobsen BM, Schittone SA, Horwitz KB. 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. doi:10.1186/bcr1340.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. DeSombre ER, Smith S, Block GE, Ferguson DJ, Jensen EV. Prediction of breast cancer response to endocrine therapy. Cancer Chemother Rep. 1974;58(4):513–9.

    CAS  PubMed  Google Scholar 

  63. Osborne CK, Schiff R. Estrogen-receptor biology: continuing progress and therapeutic implications. J Clin Oncol. 2005;23(8):1616–22. doi:10.1200/jco.2005.10.036.

    Article  CAS  PubMed  Google Scholar 

  64. Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011;62:233–47. doi:10.1146/annurev-med-070909-182917.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52. doi:10.1038/35021093.

    Article  CAS  PubMed  Google Scholar 

  66. Clarke RB, Howell A, Potten CS, Anderson E. Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res. 1997;57(22):4987–91.

    CAS  PubMed  Google Scholar 

  67. Goodman CR, Sato T, Peck AR, Girondo MA, Yang N, Liu C, et al. Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism. Oncogene. 2015. doi:10.1038/onc.2015.193.

    PubMed  Google Scholar 

  68. 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 U S A. 2010;107(50):21737–42. doi:10.1073/pnas.1007863107.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Zhou X, Wang S, Wang Z, Feng X, Liu P, Lv XB, et al. Estrogen regulates Hippo signaling via GPER in breast cancer. J Clin Invest. 2015;125(5):2123–35. doi:10.1172/jci79573.

    Article  PubMed Central  PubMed  Google Scholar 

  70. Wei W, Chen ZJ, Zhang KS, Yang XL, Wu YM, Chen XH, et al. The activation of G protein-coupled receptor 30 (GPR30) inhibits proliferation of estrogen receptor-negative breast cancer cells in vitro and in vivo. Cell Death Dis. 2014;5, e1428. doi:10.1038/cddis.2014.398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C, et al. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell. 2011;147(4):759–72. doi:10.1016/j.cell.2011.09.048.

    Article  CAS  PubMed  Google Scholar 

  72. Bartucci M, Dattilo R, Moriconi C, Pagliuca A, Mottolese M, Federici G, et al. TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells. Oncogene. 2015;34(6):681–90. doi:10.1038/onc.2014.5.

    Article  CAS  PubMed  Google Scholar 

  73. Wang Z, Zhang X, Shen P, Loggie BW, Chang Y, Deuel TF. Identification, cloning, and expression of human estrogen receptor-alpha36, a novel variant of human estrogen receptor-alpha66. Biochem Biophys Res Commun. 2005;336(4):1023–7. doi:10.1016/j.bbrc.2005.08.226.

    Article  CAS  PubMed  Google Scholar 

  74. Deng H, Yin L, Zhang XT, Liu LJ, Wang ML, Wang ZY. ER-alpha variant ER-alpha36 mediates antiestrogen resistance in ER-positive breast cancer stem/progenitor cells. J Steroid Biochem Mol Biol. 2014;144 Pt B:417–26. doi:10.1016/j.jsbmb.2014.08.017.

    Article  PubMed  CAS  Google Scholar 

  75. Deng H, Zhang XT, Wang ML, Zheng HY, Liu LJ, Wang ZY. ER-alpha36-mediated rapid estrogen signaling positively regulates ER-positive breast cancer stem/progenitor cells. PLoS One. 2014;9(2), e88034. doi:10.1371/journal.pone.0088034.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  76. Kang L, Guo Y, Zhang X, Meng J, Wang ZY. A positive cross-regulation of HER2 and ER-alpha36 controls ALDH1 positive breast cancer cells. J Steroid Biochem Mol Biol. 2011;127(3–5):262–8. doi:10.1016/j.jsbmb.2011.08.011.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Ithimakin S, Day KC, Malik F, Zen Q, Dawsey SJ, Bersano-Begey TF, et al. HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab. Cancer Res. 2013;73(5):1635–46. doi:10.1158/0008-5472.can-12-3349.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Piva M, Domenici G, Iriondo O, Rabano M, Simoes BM, Comaills V, et al. Sox2 promotes tamoxifen resistance in breast cancer cells. EMBO Mol Med. 2014;6(1):66–79. doi:10.1002/emmm.201303411.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Collins LC, Cole KS, Marotti JD, Hu R, Schnitt SJ, Tamimi RM. Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses’ Health Study. Mod Pathol. 2011;24(7):924–31. doi:10.1038/modpathol.2011.54.

    Article  PubMed Central  PubMed  Google Scholar 

  80. Niemeier LA, Dabbs DJ, Beriwal S, Striebel JM, Bhargava R. Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod Pathol. 2010;23(2):205–12. doi:10.1038/modpathol.2009.159.

    Article  CAS  PubMed  Google Scholar 

  81. Guedj M, Marisa L, de Reynies A, Orsetti B, Schiappa R, Bibeau F, et al. A refined molecular taxonomy of breast cancer. Oncogene. 2012;31(9):1196–206. doi:10.1038/onc.2011.301.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Park S, Koo JS, Kim MS, Park HS, Lee JS, Kim SI, et al. Androgen receptor expression is significantly associated with better outcomes in estrogen receptor-positive breast cancers. Ann Oncol. 2011;22(8):1755–62. doi:10.1093/annonc/mdq678.

    Article  CAS  PubMed  Google Scholar 

  83. Tsang JY, Ni YB, Chan SK, Shao MM, Law BK, Tan PH, et al. Androgen receptor expression shows distinctive significance in ER positive and negative breast cancers. Ann Surg Oncol. 2014;21(7):2218–28. doi:10.1245/s10434-014-3629-2.

    Article  PubMed  Google Scholar 

  84. Hu R, Dawood S, Holmes MD, Collins LC, Schnitt SJ, Cole K, et al. Androgen receptor expression and breast cancer survival in postmenopausal women. Clin Cancer Res. 2011;17(7):1867–74. doi:10.1158/1078-0432.ccr-10-2021.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Kuenen-Boumeester V, Van der Kwast TH, Claassen CC, Look MP, Liem GS, Klijn JG, et al. The clinical significance of androgen receptors in breast cancer and their relation to histological and cell biological parameters. Eur J Cancer. 1996;32A(9):1560–5. doi:10.1016/0959-8049(96)00112-8.

    Article  CAS  PubMed  Google Scholar 

  86. Panet-Raymond V, Gottlieb B, Beitel LK, Pinsky L, Trifiro MA. Interactions between androgen and estrogen receptors and the effects on their transactivational properties. Mol Cell Endocrinol. 2000;167(1–2):139–50. doi:10.1016/S0303-7207(00)00279-3.

    Article  CAS  PubMed  Google Scholar 

  87. Rechoum Y, Rovito D, Iacopetta D, Barone I, Ando S, Weigel NL, et al. AR collaborates with ERalpha in aromatase inhibitor-resistant breast cancer. Breast Cancer Res Treat. 2014. doi:10.1007/s10549-014-3082-8.

    Google Scholar 

  88. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011. doi:10.1172/jci45014.

    PubMed Central  PubMed  Google Scholar 

  89. Cochrane DR, Bernales S, Jacobsen BM, Cittelly DM, Howe EN, D’Amato NC, et al. Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide. Breast Cancer Res. 2014;16(1):R7. doi:10.1186/bcr3599.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  90. Barton VN, D’Amato NC, Gordon MA, Lind HT, Spoelstra NS, Babbs BL, et al. Multiple molecular subtypes of triple-negative breast cancer critically rely on androgen receptor and respond to enzalutamide in vivo. Mol Cancer Ther. 2015. doi:10.1158/1535-7163.mct-14-0926.

    PubMed Central  PubMed  Google Scholar 

  91. Chia K, O’Brien M, Brown M, Lim E. Targeting the androgen receptor in breast cancer. Curr Oncol Rep. 2015;17(2):427. doi:10.1007/s11912-014-0427-8.

    Article  CAS  Google Scholar 

  92. Nordeen SK, Kuhnel B, Lawler-Heavner J, Barber DA, Edwards DP. A quantitative comparison of dual control of a hormone response element by progestins and glucocorticoids in the same cell line. Mol Endocrinol. 1989;3(8):1270–8. doi:10.1210/mend-3-8-1270.

    Article  CAS  PubMed  Google Scholar 

  93. Barton VN, Richer JK. Androgen Receptor Biology in Triple Negative Breast Cancer: a Case for Classification as AR+ or Quadruple Negative Disease. 2015.

  94. Bentel JM, Birrell SN, Pickering MA, Holds DJ, Horsfall DJ, Tilley WD. Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells. Mol Cell Endocrinol. 1999;154(1–2):11–20. doi:10.1016/S0303-7207(99)00109-4.

    Article  CAS  PubMed  Google Scholar 

  95. Bullock LP, Bardin CW, Sherman MR. Androgenic, antiandrogenic, and synandrogenic actions of progestins: role of steric and allosteric interactions with androgen receptors. Endocrinology. 1978;103(5):1768–82. doi:10.1210/endo-103-5-1768.

    Article  CAS  PubMed  Google Scholar 

  96. Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005;114(3):448–54. doi:10.1002/ijc.20710.

    Article  CAS  PubMed  Google Scholar 

  97. Fournier A, Fabre A, Mesrine S, Boutron-Ruault MC, Berrino F, Clavel-Chapelon F. Use of different postmenopausal hormone therapies and risk of histology- and hormone receptor-defined invasive breast cancer. J Clin Oncol. 2008;26(8):1260–8. doi:10.1200/jco.2007.13.4338.

    Article  PubMed Central  PubMed  Google Scholar 

  98. 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(15):6131–40. doi:10.1158/0008-5472.can-09-0452.

    Article  CAS  PubMed  Google Scholar 

  99. McNamara KM, Moore NL, Hickey TE, Sasano H, Tilley WD. Complexities of androgen receptor signalling in breast cancer. Endocrinol Relat Cancer. 2014;21(4):T161–81. doi:10.1530/erc-14-0243.

    Article  CAS  Google Scholar 

  100. Clarke CL, Graham JD. Non-overlapping progesterone receptor cistromes contribute to cell-specific transcriptional outcomes. PLoS One. 2012;7(4), e35859. doi:10.1371/journal.pone.0035859.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  101. Haughian JM, Pinto MP, Harrell JC, Bliesner BS, Joensuu KM, Dye WW, et al. Maintenance of hormone responsiveness in luminal breast cancers by suppression of Notch. Proc Natl Acad Sci U S A. 2012;109(8):2742–7. doi:10.1073/pnas.1106509108.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  102. Faivre EJ, Lange CA. Progesterone receptors upregulate Wnt-1 to induce epidermal growth factor receptor transactivation and c-Src-dependent sustained activation of Erk1/2 mitogen-activated protein kinase in breast cancer cells. Mol Cell Biol. 2007;27(2):466–80. doi:10.1128/mcb.01539-06.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  103. Daniel AR, Qiu M, Faivre EJ, Ostrander JH, Skildum A, Lange CA. Linkage of progestin and epidermal growth factor signaling: phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth. Steroids. 2007;72(2):188–201. doi:10.1016/j.steroids.2006.11.009.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res. 2008;14(5):1368–76. doi:10.1158/1078-0432.ccr-07-1658.

    Article  CAS  PubMed  Google Scholar 

  105. Korkaya H, Paulson A, Iovino F, Wicha MS. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene. 2008;27(47):6120–30. doi:10.1038/onc.2008.207.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  106. Knutson TP, Daniel AR, Fan D, Silverstein KA, Covington KR, Fuqua SA, et al. Phosphorylated and sumoylation-deficient progesterone receptors drive proliferative gene signatures during breast cancer progression. Breast Cancer Res. 2012;14(3):R95. doi:10.1186/bcr3211.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Sato T, Tran TH, Peck AR, Girondo MA, Liu C, Goodman CR, et al. Prolactin suppresses a progestin-induced CK5-positive cell population in luminal breast cancer through inhibition of progestin-driven BCL6 expression. Oncogene. 2014;33(17):2215–24. doi:10.1038/onc.2013.172.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. Tran TH, Utama FE, Lin J, Yang N, Sjolund AB, Ryder A, et al. Prolactin inhibits BCL6 expression in breast cancer through a Stat5a-dependent mechanism. Cancer Res. 2010;70(4):1711–21. doi:10.1158/0008-5472.can-09-2314.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  109. Liu R, Zhou Z, Zhao D, Chen C. The induction of KLF5 transcription factor by progesterone contributes to progesterone-induced breast cancer cell proliferation and dedifferentiation. Mol Endocrinol. 2011;25(7):1137–44. doi:10.1210/me.2010-0497.

    Article  CAS  PubMed  Google Scholar 

  110. Izzo F, Mercogliano F, Venturutti L, Tkach M, Inurrigarro G, Schillaci R, et al. Progesterone receptor activation downregulates GATA3 by transcriptional repression and increased protein turnover promoting breast tumor growth. Breast Cancer Res. 2014;16(6):491. doi:10.1186/s13058-014-0491-x.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  111. Anzano MA, Byers SW, Smith JM, Peer CW, Mullen LT, Brown CC, et al. Prevention of breast cancer in the rat with 9-cis-retinoic acid as a single agent and in combination with tamoxifen. Cancer Res. 1994;54(17):4614–7.

    CAS  PubMed  Google Scholar 

  112. Clarke CL, Graham J, Roman SD, Sutherland RL. Direct transcriptional regulation of the progesterone receptor by retinoic acid diminishes progestin responsiveness in the breast cancer cell line T-47D. J Biol Chem. 1991;266(28):18969–75.

    CAS  PubMed  Google Scholar 

  113. Clarke CL, Roman SD, Graham J, Koga M, Sutherland RL. Progesterone receptor regulation by retinoic acid in the human breast cancer cell line T-47D. J Biol Chem. 1990;265(21):12694–700.

    CAS  PubMed  Google Scholar 

  114. Klinge CM. miRNAs regulated by estrogens, tamoxifen, and endocrine disruptors and their downstream gene targets. Mol Cell Endocrinol. 2015. doi:10.1016/j.mce.2015.01.035.

    PubMed  Google Scholar 

  115. 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. doi:10.1016/j.mce.2011.12.020.

    Article  CAS  PubMed  Google Scholar 

  116. Tessel MA, Krett NL, Rosen ST. Steroid receptor and microRNA regulation in cancer. Curr Opin Oncol. 2010;22(6):592–7. doi:10.1097/CCO.0b013e32833ea80c.

    Article  CAS  PubMed  Google Scholar 

  117. Fletcher CE, Dart DA, Bevan CL. Interplay between steroid signalling and microRNAs: implications for hormone-dependent cancers. Endocrinol Relat Cancer. 2014;21(5):R409–29. doi:10.1530/erc-14-0208.

    Article  CAS  Google Scholar 

  118. Chou J, Lin JH, Brenot A, Kim JW, Provot S, Werb Z. GATA3 suppresses metastasis and modulates the tumour microenvironment by regulating microRNA-29b expression. Nat Cell Biol. 2013;15(2):201–13. doi:10.1038/ncb2672.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  119. Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D, et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell. 2009;138(3):592–603. doi:10.1016/j.cell.2009.07.011.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  120. Bussing I, Slack FJ, Grosshans H. let-7 microRNAs in development, stem cells and cancer. Trends Mol Med. 2008;14(9):400–9. doi:10.1016/j.molmed.2008.07.001.

    Article  PubMed  CAS  Google Scholar 

  121. Di Leva G, Gasparini P, Piovan C, Ngankeu A, Garofalo M, Taccioli C, et al. MicroRNA cluster 221–222 and estrogen receptor alpha interactions in breast cancer. J Natl Cancer Inst. 2010;102(10):706–21. doi:10.1093/jnci/djq102.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  122. Cochrane DR, Howe EN, Spoelstra NS, Richer JK. Loss of miR-200c: a marker of aggressiveness and chemoresistance in female reproductive cancers. J Oncol. 2010;2010:821717. doi:10.1155/2010/821717.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  123. Lyu S, Yu Q, Ying G, Wang S, Wang Y, Zhang J, et al. Androgen receptor decreases CMYC and KRAS expression by upregulating let-7a expression in ER-, PR-, AR+ breast cancer. Int J Oncol. 2014;44(1):229–37. doi:10.3892/ijo.2013.2151.

    Article  CAS  PubMed  Google Scholar 

  124. Nakano K, Miki Y, Hata S, Ebata A, Takagi K, McNamara KM, et al. Identification of androgen-responsive microRNAs and androgen-related genes in breast cancer. Anticancer Res. 2013;33(11):4811–9.

    CAS  PubMed  Google Scholar 

  125. Reid BG, Jerjian T, Patel P, Zhou Q, Yoo BH, Kabos P, et al. Live multicellular tumor spheroid models for high-content imaging and screening in cancer drug discovery. Curr Chem Genomics Transl Med. 2014;8 Suppl 1:27–35. doi:10.2174/2213988501408010027.

    Article  PubMed Central  PubMed  Google Scholar 

  126. 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. doi:10.1038/nature09387.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  127. 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. doi:10.1038/nature09495.

    Article  CAS  PubMed  Google Scholar 

  128. 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. doi:10.15252/embj.201490434.

    Article  CAS  PubMed  Google Scholar 

  129. Shiah YJ, 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(3):313–22. doi:10.1016/j.stemcr.2015.01.011.

    Article  CAS  Google Scholar 

  130. Tanos T, Sflomos G, Echeverria PC, Ayyanan A, Gutierrez M, Delaloye JF, et al. Progesterone/RANKL is a major regulatory axis in the human breast. Sci Transl Med. 2013;5(182):182ra55. doi:10.1126/scitranslmed.3005654.

    Article  PubMed  CAS  Google Scholar 

  131. 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. doi:10.1074/jbc.M110090200.

    Article  CAS  PubMed  Google Scholar 

  132. Jacobsen BM, Schittone SA, Richer JK, Horwitz KB. Progesterone-independent effects of human progesterone receptors (PRs) in estrogen receptor-positive breast cancer: PR isoform-specific gene regulation and tumor biology. Mol Endocrinol. 2005;19(3):574–87. doi:10.1210/me.2004-0287.

    Article  CAS  PubMed  Google Scholar 

  133. 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. doi:10.1158/0008-5472.can-12-0044.

    Article  CAS  PubMed  Google Scholar 

  134. 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. doi:10.1016/j.stemcr.2014.05.005.

    Article  CAS  Google Scholar 

  135. Ablett MP, O’Brien CS, Sims AH, Farnie G, Clarke RB. A differential role for CXCR4 in the regulation of normal versus malignant breast stem cell activity. Oncotarget. 2014;5(3):599–612.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by grants NIH R01 CA140985 (CAS) and NIH 1F32CA177081 (JFS). The authors wish to apologize to those whose work was not referenced due to space limitations.

Author information

Authors and Affiliations

  1. Department of Pathology, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue; MS 8104, Aurora, CO, 80045, USA

    Jessica Finlay-Schultz & Carol A. Sartorius

Authors
  1. Jessica Finlay-Schultz
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Carol A. Sartorius
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Jessica Finlay-Schultz.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Finlay-Schultz, J., Sartorius, C.A. Steroid Hormones, Steroid Receptors, and Breast Cancer Stem Cells. J Mammary Gland Biol Neoplasia 20, 39–50 (2015). https://doi.org/10.1007/s10911-015-9340-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10911-015-9340-5

Keywords