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01-08-2011 | Preclinical study

Effects of estrogen on the proportion of stem cells in the breast

Authors: Bruno M. Simões, Marco Piva, Oihana Iriondo, Valentine Comaills, Jose A. López-Ruiz, Iñaki Zabalza, Jon A. Mieza, Olga Acinas, Maria d.M. Vivanco

Published in: Breast Cancer Research and Treatment | Issue 1/2011

Abstract

There is increasing evidence that breast cancers contain tumor-initiating cells with stem cell properties. The importance of estrogen in the development of the mammary gland and in breast cancer is well known, but the influence of estrogen on the stem cell population has not been assessed. We show that estrogen reduces the proportion of stem cells in the normal human mammary gland and in breast cancer cells. The embryonic stem cell genes NANOG, OCT4, and SOX2 are expressed in normal breast stem cells and at higher levels in breast tumor cells and their expression decreases upon differentiation. Overexpression of each stem cell gene reduces estrogen receptor (ER) expression, and increases the number of stem cells and their capacity for invasion, properties associated with tumorigenesis and poor prognosis. These results indicate that estrogen reduces the size of the human breast stem cell pool and may provide an explanation for the better prognosis of ER-positive tumors.

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Bocchinfuso WP, Lindzey JK, Hewitt SC, Clark JA, Myers PH, Cooper R, Korach KS (2000) Induction of mammary gland development in estrogen receptor-alpha knockout mice. Endocrinology 141(8):2982–2994PubMedCrossRef

Ali S, Coombes RC (2002) Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer 2(2):101–112PubMedCrossRef

Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, Martiat P, Fox SB, Harris AL, Liu ET (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA 100(18):10393–10398PubMedCrossRef

van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, van der Velde T, Bartelink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347(25):1999–2009PubMedCrossRef

Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874PubMedCrossRef

Dontu G, El-Ashry D, Wicha MS (2004) Breast cancer, stem/progenitor cells and the estrogen receptor. Trends Endocrinol Metab 15(5):193–197PubMedCrossRef

LaMarca HL, Rosen JM (2008) Minireview: hormones and mammary cell fate—what will I become when I grow up? Endocrinology 149(9):4317–4321PubMedCrossRef

Clayton H, Titley I, Vivanco M (2004) Growth and differentiation of progenitor/stem cells derived from the human mammary gland. Exp Cell Res 297(2):444–460PubMedCrossRef

Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, Wicha MS (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17(10):1253–1270PubMedCrossRef

10.

Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, Pilotti S, Pierotti MA, Daidone MG (2005) Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 65(13):5506–5511PubMedCrossRef

11.

Farnie G, Clarke RB, Spence K, Pinnock N, Brennan K, Anderson NG, Bundred NJ (2007) Novel cell culture technique for primary ductal carcinoma in situ: Role of notch and epidermal growth factor receptor signaling pathways. J Natl Cancer Inst 99(8):616–627PubMedCrossRef

12.

Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988PubMedCrossRef

13.

Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, Halushka MK, Sukumar S, Parker LM, Anderson KS, Harris LN, Garber JE, Richardson AL, Schnitt SJ, Nikolsky Y, Gelman RS, Polyak K (2007) Molecular definition of breast tumor heterogeneity. Cancer Cell 11(3):259–273PubMedCrossRef

14.

Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G (2007) Aldh1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1(5):555–567PubMedCrossRef

15.

Wong DJ, Liu H, Ridky TW, Cassarino D, Segal E, Chang HY (2008) Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell 2(4):333–344PubMedCrossRef

16.

Niwa H (2007) How is pluripotency determined and maintained? Development 134(4):635–646PubMedCrossRef

17.

Surani MA, Hayashi K, Hajkova P (2007) Genetic and epigenetic regulators of pluripotency. Cell 128(4):747–762PubMedCrossRef

18.

Riekstina U, Cakstina I, Parfejevs V, Hoogduijn M, Jankovskis G, Muiznieks I, Muceniece R, Ancans J (2009) Embryonic stem cell marker expression pattern in human mesenchymal stem cells derived from bone marrow, adipose tissue, heart and dermis. Stem Cell Rev Rep 5(4):378–386CrossRef

19.

Ling TY, Kuo MD, Li CL, Yu AL, Huang YH, Wu TJ, Lin YC, Chen SH, Yu J (2006) Identification of pulmonary oct-4 + stem/progenitor cells and demonstration of their susceptibility to sars coronavirus (sars-cov) infection in vitro. Proc Natl Acad Sci USA 103(25):9530–9535PubMedCrossRef

20.

Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A, Weinberg RA (2008) An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40(5):499–507PubMedCrossRef

21.

Gascoyne DM, Hixon ML, Gualberto A, Vivanco MD (2003) Loss of mitotic spindle checkpoint activity predisposes to chromosomal instability at early stages of fibrosarcoma development. Cell Cycle 2(3):238–245PubMedCrossRef

22.

Ricketts D, Turnbull L, Ryall G, Bakhshi R, Rawson NS, Gazet JC, Nolan C, Coombes RC (1991) Estrogen and progesterone receptors in the normal female breast. Cancer Res 51(7):1817–1822PubMed

23.

Vivanco MD, Johnson R, Galante PE, Hanahan D, Yamamoto KR (1995) A transition in transcriptional activation by the glucocorticoid and retinoic acid receptors at the tumor stage of dermal fibrosarcoma development. EMBO J 14(10):2217–2228PubMed

24.

Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner RG, Gifford DK, Melton DA, Jaenisch R, Young RA (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122(6):947–956PubMedCrossRef

25.

Kok M, Koornstra RH, Margarido TC, Fles R, Armstrong NJ, Linn SC, Van’t Veer LJ, Weigelt B (2009) Mammosphere-derived gene set predicts outcome in patients with er-positive breast cancer. J Pathol 218(3):316–326PubMedCrossRef

26.

Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, Asselin-Labat ML, Gyorki DE, Ward T, Partanen A, Feleppa F, Huschtscha LI, Thorne HJ, Fox SB, Yan M, French JD, Brown MA, Smyth GK, Visvader JE, Lindeman GJ (2009) Aberrant luminal progenitors as the candidate target population for basal tumor development in brca1 mutation carriers. Nat Med 15(8):907–913PubMedCrossRef

27.

Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448(7151):313–317PubMedCrossRef

28.

Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R (2007) In vitro reprogramming of fibroblasts into a pluripotent es-cell-like state. Nature 448(7151):318–324PubMedCrossRef

29.

Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676PubMedCrossRef

30.

Kalmar T, Lim C, Hayward P, Munoz-Descalzo S, Nichols J, Garcia-Ojalvo J, Martinez Arias A (2009) Regulated fluctuations in nanog expression mediate cell fate decisions in embryonic stem cells. PLoS Biol 7(7):e1000149PubMedCrossRef

31.

Badve S, Nakshatri H (2009) Oestrogen-receptor-positive breast cancer: Towards bridging histopathological and molecular classifications. J Clin Pathol 62(1):6–12PubMedCrossRef

32.

Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz i Altaba A (2007) Hedgehog-gli1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 17(2):165–172PubMedCrossRef

33.

Rodriguez-Pinilla SM, Sarrio D, Moreno-Bueno G, Rodriguez-Gil Y, Martinez MA, Hernandez L, Hardisson D, Reis-Filho JS, Palacios J (2007) Sox2: a possible driver of the basal-like phenotype in sporadic breast cancer. Mod Pathol 20(4):474–481PubMedCrossRef

34.

Ezeh UI, Turek PJ, Reijo RA, Clark AT (2005) Human embryonic stem cell genes oct4, nanog, stellar, and gdf3 are expressed in both seminoma and breast carcinoma. Cancer 104(10):2255–2265PubMedCrossRef

35.

Jeter CR, Badeaux M, Choy G, Chandra D, Patrawala L, Liu C, Calhoun-Davis T, Zaehres H, Daley GQ, Tang DG (2009) Functional evidence that the self-renewal gene nanog regulates human tumor development. Stem Cells 27(5):993–1005PubMedCrossRef

36.

Chen Y, Shi L, Zhang L, Li R, Liang J, Yu W, Sun L, Yang X, Wang Y, Zhang Y, Shang Y (2008) The molecular mechanism governing the oncogenic potential of sox2 in breast cancer. J Biol Chem 283(26):17969–17978PubMedCrossRef

37.

Liu R, Wang X, Chen GY, Dalerba P, Gurney A, Hoey T, Sherlock G, Lewicki J, Shedden K, Clarke MF (2007) The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med 356(3):217–226PubMedCrossRef

38.

Shipitsin M, Polyak K (2008) The cancer stem cell hypothesis: in search of definitions, markers, and relevance. Lab Invest 88(5):459–463PubMedCrossRef

39.

Sheridan C, Kishimoto H, Fuchs RK, Mehrotra S, Bhat-Nakshatri P, Turner CH, Goulet R Jr, Badve S, Nakshatri H (2006) Cd44+/cd24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res 8(5):R59PubMedCrossRef

40.

Abraham BK, Fritz P, McClellan M, Hauptvogel P, Athelogou M, Brauch H (2005) Prevalence of cd44+/cd24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res 11(3):1154–1159PubMed

41.

Charafe-Jauffret E, Ginestier C, Iovino F, Tarpin C, Diebel M, Esterni B, Houvenaeghel G, Extra JM, Bertucci F, Jacquemier J, Xerri L, Dontu G, Stassi G, Xiao Y, Barsky SH, Birnbaum D, Viens P, Wicha MS (2010) Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin Cancer Res 16(1):45–55

42.

Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC, Wong H, Rosen J, Chang JC (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100(9):672–679PubMedCrossRef

43.

Pece S, Tosoni D, Confalonieri S, Mazzarol G, Vecchi M, Ronzoni S, Bernard L, Viale G, Pelicci PG, Di Fiore PP (2010) Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell 140(1):62–73

44.

Vivanco M (2010) Function follows form: defining mammary stem cells. Sci Transl Med 2(31):31ps22

45.

Ciarloni L, Mallepell S, Brisken C (2007) Amphiregulin is an essential mediator of estrogen receptor alpha function in mammary gland development. Proc Natl Acad Sci USA 104(13):5455–5460PubMedCrossRef

46.

LaMarca HL, Rosen JM (2007) Estrogen regulation of mammary gland development and breast cancer: amphiregulin takes center stage. Breast Cancer Res 9(4):304PubMedCrossRef

47.

Clemons M, Goss P (2001) Estrogen and the risk of breast cancer. N Engl J Med 344(4):276–285PubMedCrossRef

48.

Lewis-Wambi JS, Jordan VC (2009) Estrogen regulation of apoptosis: how can one hormone stimulate and inhibit? Breast Cancer Res 11(3):206PubMedCrossRef

49.

Britt K, Ashworth A, Smalley M (2007) Pregnancy and the risk of breast cancer. Endocr Relat Cancer 14(4):907–933PubMedCrossRef

50.

Polyak K (2006) Pregnancy and breast cancer: the other side of the coin. Cancer Cell 9(3):151–153PubMedCrossRef

51.

Deroo BJ, Hewitt SC, Collins JB, Grissom SF, Hamilton KJ, Korach KS (2009) Profile of estrogen-responsive genes in an estrogen-specific mammary gland outgrowth model. Mol Reprod Dev 76(8):733–750PubMedCrossRef

52.

Ellis MJ, Gao F, Dehdashti F, Jeffe DB, Marcom PK, Carey LA, Dickler MN, Silverman P, Fleming GF, Kommareddy A, Jamalabadi-Majidi S, Crowder R, Siegel BA (2009) Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. JAMA 302(7):774–780PubMedCrossRef

53.

Schneider J, Martin-Gutierrez S, Tresguerres JA, Garcia-Velasco JA (2009) Circulating estradiol defines the tumor phenotype in menopausal breast cancer patients. Maturitas 64(1):43–45PubMedCrossRef

54.

Liu S, Ginestier C, Charafe-Jauffret E, Foco H, Kleer CG, Merajver SD, Dontu G, Wicha MS (2008) Brca1 regulates human mammary stem/progenitor cell fate. Proc Natl Acad Sci USA 105(5):1680–1685PubMedCrossRef

55.

Kurian AW, McClure LA, John EM, Horn-Ross PL, Ford JM, Clarke CA (2009) Second primary breast cancer occurrence according to hormone receptor status. J Natl Cancer Inst 101(15):1058–1065PubMedCrossRef

56.

Zhou L, Jiang Y, Yan T, Di G, Shen Z, Shao Z, Lu J (2010) The prognostic role of cancer stem cells in breast cancer: a meta-analysis of published literatures. Breast Cancer Res Treat 122(3):795–801

57.

Rajkumar L, Kittrell FS, Guzman RC, Brown PH, Nandi S, Medina D (2007) Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models. Breast Cancer Res 9(1):R12PubMedCrossRef

58.

Asselin-Labat ML, Vaillant F, Sheridan JM, Pal B, Wu D, Simpson ER, Yasuda H, Smyth GK, Martin TJ, Lindeman GJ, Visvader JE (2010) Control of mammary stem cell function by steroid hormone signalling. Nature 465(7299):798–802

59.

Joshi PA, Jackson HW, Beristain AG, Di Grappa MA, Mote PA, Clarke CL, Stingl J, Waterhouse PD, Khokha R (2010) Progesterone induces adult mammary stem cell expansion. Nature 465(7299):803–807

60.

Britt KL, Kendrick H, Regan JL, Molyneux G, Magnay FA, Ashworth A, Smalley MJ (2009) Pregnancy in the mature adult mouse does not alter the proportion of mammary epithelial stem/progenitor cells. Breast Cancer Res 11(2):R20PubMedCrossRef

61.

Siwko SK, Dong J, Lewis MT, Liu H, Hilsenbeck SG, Li Y (2008) Evidence that an early pregnancy causes a persistent decrease in the number of functional mammary epithelial stem cells—implications for pregnancy-induced protection against breast cancer. Stem Cells 26(12):3205–3209PubMedCrossRef

Title: Effects of estrogen on the proportion of stem cells in the breast
Authors: Bruno M. Simões
Marco Piva
Oihana Iriondo
Valentine Comaills
Jose A. López-Ruiz
Iñaki Zabalza
Jon A. Mieza
Olga Acinas
Maria d.M. Vivanco
Publication date: 01-08-2011
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2011
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-010-1169-4

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