Breast Cancer Research and Treatment

, Volume 89, Issue 3, pp 297–304 | Cite as

The “portrait” of hereditary breast cancer

Review

Summary

Five to ten per cent of all breast carcinomas are of hereditary origin. Many of them have been associated to mutations in the BRCA1 and BRCA2 susceptibility genes. No “BRCA3” gene has been found to account for the non-BRCA1/BRCA2 breast cancer (BRCAx) families, and BRCAx tumors are increasingly believed to originate from multiple distinct genetic events. Phenotype studies have questioned the existence of specific “portraits” among hereditary breast carcinomas (HBC). They have shown that most BRCA1 tumors have a “basal (epithelial)-like” aspect, while BRCA2 and BRCAx HBC are more heterogeneous. HBC have also been submitted to genetic analyses, notably with the objective of resolving the heterogeneity of BRCAx lesions. The present review aims to summarize recent data on BRCA1, BRCA2, and BRCAx HBC, including hypotheses on the origin of BRCA1 tumors and their paradoxical relations to estrogen-sensitivity.

Keywords

basal BRCA1 BRCA2 BRCAx estrogen receptor genotype hereditary cancer luminal phenotype p53 

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References

  1. Carter, RF 2001BRCA1, BRCA2 and breast cancer: a concise clinical reviewClin Invest Med24147157PubMedGoogle Scholar
  2. Borg, A 2001Molecular and pathological characterization of inherited breast cancerSemin Cancer Biol11375385PubMedGoogle Scholar
  3. Iau, PT, Macmillan, RD, Blamey, RW 2001Germ line mutations associated with breast cancer susceptibilityEur J Cancer37300321PubMedGoogle Scholar
  4. Welcsh, PL, King, MC 2001BRCA1 and BRCA2 and the genetics of breast and ovarian cancerHum Mol Genet10705713CrossRefPubMedGoogle Scholar
  5. Starita, LM, Parvin, JD 2003The multiple nuclear functions of BRCA1: transcription, ubiquitination and DNA repairCurr Opin Cell Biol15345350PubMedGoogle Scholar
  6. Rosen, EM, Fan, S, Pestell, RG, Goldberg, ID 2003BRCA1 gene in breast cancerJ Cell Physiol1961941PubMedGoogle Scholar
  7. Powell, SN, Kachnic, LA 2003Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiationOncogene2257845791PubMedGoogle Scholar
  8. Moynahan, ME, Chiu, JW, Koller, BH, Jasin, M 1999Brca1 controls homology-directed DNA repairMol Cell4511518PubMedGoogle Scholar
  9. Zhong, Q, Chen, CF, Chen, PL, Lee, WH 2002BRCA1 facilitates microhomology-mediated end joining of DNA double strand breaksJ Biol Chem2772864128647PubMedGoogle Scholar
  10. Tutt, A, Ashworth, A 2002The relationship between the roles of BRCA genes in DNA repair and cancer predispositionTrends Mol Med8571576PubMedGoogle Scholar
  11. Rajan, JV, Wang, M, Marquis, ST, Chodosh, LA 1996Brca2 is coordinately regulated with Brca1 during proliferation and differentiation in mammary epithelial cellsProc Natl Acad Sci USA931307813083PubMedGoogle Scholar
  12. Chen, Y, Farmer, AA, Chen, CF, Jones, DC, Chen, PL, Lee, WH 1996BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent mannerCancer Res5631683172PubMedGoogle Scholar
  13. Ruffner, H, Verma, IM 1997BRCA1 is a cell cycle-regulated nuclear phosphoproteinProc Natl Acad Sci USA9471387143PubMedGoogle Scholar
  14. Vissac, C, Peffault, DL, Communal, Y, Bignon, YJ, Bernard-Gallon, DJ 2002Expression of BRCA1 and BRCA2 in different tumor cell lines with various growth statusClin Chim Acta320101110PubMedGoogle Scholar
  15. Spillman, MA, Bowcock, AM 1996BRCA1 and BRCA2 mRNA levels are coordinately elevated in human breast cancer cells in response to estrogenOncogene1316391645PubMedGoogle Scholar
  16. Favy, DA, Rio, P, Maurizis, JC, Hizel, C, Bignon, YJ, Bernard-Gallon, DJ 1999Prolactin-dependent up-regulation of BRCA1 expression in human breast cancer cell linesBiochem Biophys Res Commun258284291PubMedGoogle Scholar
  17. Fan, S, Wang, J, Yuan, R, Ma, Y, Meng, Q, Erdos, MR, Pestell, RG, Yuan, F, Auborn, KJ, Goldberg, ID, Rosen, EM 1999BRCA1 inhibition of estrogen receptor signaling in transfected cellsScience28413541356PubMedGoogle Scholar
  18. Wang, Q, Zhang, H, Kajino, K, Greene, MI 1998BRCA1 binds c-Myc and inhibits its transcriptional and transforming activity in cellsOncogene1719391948PubMedGoogle Scholar
  19. Vidarsson, H, Mikaelsdottir, EK, Rafnar, T, Bertwistle, D, Ashworth, A, Eyfjord, JE, Valgeirsdottir, S 2002BRCA1 and BRCA2 bind Stat5a and suppress its transcriptional activityFEBS Lett532247252PubMedGoogle Scholar
  20. Fan, S, Ma, YX, Wang, C, Yuan, RQ, Meng, Q, Wang, JA, Erdos, M, Goldberg, ID, Webb, P, Kushner, PJ, Pestell, RG, Rosen, EM 2002p300 modulates the BRCA1 inhibition of estrogen receptor activityCancer Res62141151PubMedGoogle Scholar
  21. Pfitzner, E, Jahne, R, Wissler, M, Stoecklin, E, Groner, B 1998p300/CREB-binding protein enhances the prolactin-mediated transcriptional induction through direct interaction with the transactivation domain of Stat5, but does not participate in the Stat5-mediated suppression of the glucocorticoid responseMol Endocrinol1215821593CrossRefPubMedGoogle Scholar
  22. Kubista, M, Rosner, M, Miloloza, A, Hofer, K, Prusa, AR, Kroiss, R, Marton, E, Hengstschlager, M 2002Brca1 and differentiationMutat Res512165172PubMedGoogle Scholar
  23. Nathanson, KL, Weber, BL 2001“Other” breast cancer susceptibility genes: searching for more holy grailHum Mol Genet10715720PubMedGoogle Scholar
  24. Weber, BL, Nathanson, KL 2000Low penetrance genes associated with increased risk for breast cancerEur J Cancer3611931199PubMedGoogle Scholar
  25. Bonadona, V, Lasset, C 2003Inherited predisposition to breast cancer: after the BRCA1 and BRCA2 genes, what next?Bull Cancer90587594PubMedGoogle Scholar
  26. Consortium, Breast Cancer Linkage 1997Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic casesLancet34915051510Google Scholar
  27. Phillips, KA 2000Immunophenotypic and pathologic differences between BRCA1 and BRCA2 hereditary breast cancersJ Clin Oncol18107S112SPubMedGoogle Scholar
  28. Lakhani, SR, Gusterson, BA, Jacquemier, J, Sloane, JP, Anderson, TJ, Vijver, MJ, Venter, D, Freeman, A, Antoniou, A, McGuffog, L, Smyth, E, Steel, CM, Haites, N, Scott, RJ, Goldgar, D, Neuhausen, S, Daly, PA, Ormiston, W, McManus, R, Scherneck, S, Ponder, BA, Futreal, PA, Peto, J, Stoppa-Lyonnet, D, Bignon, YJ, Stratton, MR 2000The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2Clin Cancer Res6782789PubMedGoogle Scholar
  29. Paredes, J, Milanezi, F, Viegas, L, Amendoeira, I, Schmitt, F 2002P-cadherin expression is associated with high-grade ductal carcinoma in situ of the breastVirchows Arch4401621PubMedGoogle Scholar
  30. Grushko, TA, Blackwood, MA, Schumm, PL, Hagos, FG, Adeyanju, MO, Feldman, MD, Sanders, MO, Weber, BL, Olopade, OI 2002Molecular-cytogenetic analysis of HER-2/neu gene in BRCA1-associated breast cancersCancer Res6214811488PubMedGoogle Scholar
  31. Lakhani, SR, Vijver, MJ, Jacquemier, J, Anderson, TJ, Osin, PP, McGuffog, L, Easton, DF 2002The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2J Clin Oncol2023102318PubMedGoogle Scholar
  32. Berns, EM, Dirkzwager-Kiel, MJ, Kuenen-Boumeester, V, Timmermans, M, Verhoog, LC, Ouweland, AM, Meijer-Heijboer, H, Klijn, JG, Kwast, TH 2003Androgen pathway dysregulation in BRCA1-mutated breast tumorsBreast Cancer Res Treat79121127PubMedGoogle Scholar
  33. Foulkes, WD, Stefansson, IM, Chappuis, PO, Begin, LR, Goffin, JR, Wong, N, Trudel, M, Akslen, LA 2003Germline BRCA1 mutations and a basal epithelial phenotype in breast cancerJ Natl Cancer Inst9514821485PubMedGoogle Scholar
  34. Foulkes, WD, Metcalfe, K, Hanna, W, Lynch, HT, Ghadirian, P, Tung, N, Olopade, O, Weber, B, McLennan, J, Olivotto, IA, Sun, P, Chappuis, PO, Begin, LR, Brunet, JS, Narod, SA 2003Disruption of the expected positive correlation between breast tumor size and lymph node status in BRCA1-related breast carcinomaCancer9815691577PubMedGoogle Scholar
  35. Goffin, JR, Straume, O, Chappuis, PO, Brunet, JS, Begin, LR, Hamel, N, Wong, N, Akslen, LA, Foulkes, WD 2003Glomeruloid microvascular proliferation is associated with p53 expression, germline BRCA1 mutations and an adverse outcome following breast cancerBr J Cancer8910311034PubMedGoogle Scholar
  36. Palacios, J, Honrado, E, Osorio, A, Cazorla, A, Sarrio, D, Barroso, A, Rodriguez, S, Cigudosa, JC, Diez, O, Alonso, C, Lerma, E, Sanchez, L, Rivas, C, Benitez, J 2003Immunohistochemical characteristics defined by tissue microarray of hereditary breast cancer not attributable to BRCA1 or BRCA2 mutations: differences from breast carcinomas arising in BRCA1 and BRCA2 mutation carriersClin Cancer Res936063614PubMedGoogle Scholar
  37. Sensi, E, Tancredi, M, Aretini, P, Cipollini, G, Naccarato, AG, Viacava, P, Bevilacqua, G, Caligo, MA 2003p53 inactivation is a rare event in familial breast tumors negative for BRCA1 and BRCA2 mutationsBreast Cancer Res Treat8219PubMedGoogle Scholar
  38. Foulkes, WD, Brunet, JS, Stefansson, IM, Straume, O, Chappuis, PO, Begin, LR, Hamel, N, Goffin, JR, Wong, N, Trudel, M, Kapusta, L, Porter, P, Akslen, LA 2004The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancerCancer Res64830835PubMedGoogle Scholar
  39. Tomlinson, GE, Chen, TT, Stastny, VA, Virmani, AK, Spillman, MA, Tonk, V, Blum, JL, Schneider, NR, Wistuba, II, Shay, JW, Minna, JD, Gazdar, AF 1998Characterization of a breast cancer cell line derived from a germ-line BRCA1 mutation carrierCancer Res5832373242PubMedGoogle Scholar
  40. Johannsson, OT, Staff, S, Vallon-Christersson, J, Kytola, S, Gudjonsson, T, Rennstam, K, Hedenfalk, IA, Adeyinka, A, Kjellen, E, Wennerberg, J, Baldetorp, B, Petersen, OW, Olsson, H, Oredsson, S, Isola, J, Borg, A 2003Characterization of a novel breast carcinoma xenograft and cell line derived from a BRCA1 germ-line mutation carrierLab Invest83387396PubMedGoogle Scholar
  41. Lacroix, M, Leclercq, G 2004Relevance of breast cancer cell lines as models for breast tumours: an updateBreast Cancer Res Treat83249289PubMedGoogle Scholar
  42. Sorlie, T, Tibshirani, R, Parker, J, Hastie, T, Marron, JS, Nobel, A, Deng, S, Johnsen, H, Pesich, R, Geisler, S, Demeter, J, Perou, CM, Lonning, PE, Brown, PO, Borresen-Dale, AL, Botstein, D 2003Repeated observation of breast tumor subtypes in independent gene expression data setsProc Natl Acad Sci USA10084188423PubMedGoogle Scholar
  43. Korsching, E, Packeisen, J, Agelopoulos, K, Eisenacher, M, Voss, R, Isola, J, Diest, PJ, Brandt, B, Boecker, W, Buerger, H 2002Cytogenetic alterations and cytokeratin expression patterns in breast cancer: integrating a new model of breast differentiation into cytogenetic pathways of breast carcinogenesisLab Invest8215251533PubMedGoogle Scholar
  44. Veer, LJ, Dai, H, Vijver, MJ, He, YD, Hart, AA, Mao, M, Peterse, HL, der, KK, Marton, MJ, Witteveen, AT, Schreiber, GJ, Kerkhoven, RM, Roberts, C, Linsley, PS, Bernards, R, Friend, SH 2002Gene expression profiling predicts clinical outcome of breast cancerNature415530536CrossRefPubMedGoogle Scholar
  45. Riju, M, Perou, CM, Tibshirani, R, Haas, P, Kallioniemi, O, Kononen, J, Torhorst, J, Sauter, G, Zuber, M, Kochli, OR, Mross, F, Dieterich, H, Seitz, R, Ross, D, Botstein, D, Brown, P 2002Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcomeAm J Pathol16119911996PubMedGoogle Scholar
  46. Lacroix, M, Toillon, RA, Leclercq, G 2004Stable ‘portrait’ of breast tumors during progression. Data from biology, pathology, and geneticsEndocr Relat Cancer11497523PubMedGoogle Scholar
  47. Hughes-Davies, L, Huntsman, D, Ruas, M, Fuks, F, Bye, J, Chin, SF, Milner, J, Brown, LA, Hsu, F, Gilks, B, Nielsen, T, Schulzer, M, Chia, S, Ragaz, J, Cahn, A, Linger, L, Ozdag, H, Cattaneo, E, Jordanova, ES, Schuuring, E, Yu, DS, Venkitaraman, A, Ponder, B, Doherty, A, Aparicio, S, Bentley, D, Theillet, C, Ponting, CP, Caldas, C, Kouzarides, T 2003EMSY links the BRCA2 pathway to sporadic breast and ovarian cancerCell115523535PubMedGoogle Scholar
  48. Hedenfalk, I, Duggan, D, Chen, Y, Radmacher, M, Bittner, M, Simon, R, Meltzer, P, Gusterson, B, Esteller, M, Kallioniemi, OP, Wilfond, B, Borg, A, Trent, J 2001Gene-expression profiles in hereditary breast cancerN Engl J Med344539548PubMedGoogle Scholar
  49. Hedenfalk, I, Ringner, M, Ben Dor, A, Yakhini, Z, Chen, Y, Chebil, G, Ach, R, Loman, N, Olsson, H, Meltzer, P, Borg, A, Trent, J 2003Molecular classification of familial non-BRCA1/BRCA2 breast cancerProc Natl Acad Sci USA10025322537PubMedGoogle Scholar
  50. Hohenstein, P, Giles, RH 2003BRCA1: a scaffold for p53 responseTrends Genet19489494PubMedGoogle Scholar
  51. Brodie, SG, Xu, X, Qiao, W, Li, WM, Cao, L, Deng, CX 2001Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout miceOncogene2075147523PubMedGoogle Scholar
  52. Greenblatt, MS, Chappuis, PO, Bond, JP, Hamel, N, Foulkes, WD 2001TP53 mutations in breast cancer associated with BRCA1 or BRCA2 germ-line mutations: distinctive spectrum and structural distributionCancer Res6140924097PubMedGoogle Scholar
  53. Foulkes, WD, Metcalfe, K, Sun, P, Hanna, WM, Lynch, HT, Ghadirian, P, Tung, N, Olopade, OI, Weber, BL, McLennan, J, Olivotto, IA, Begin, LR, Narod, SA 2004Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence of age, grade, and histological typeClin Cancer Res1020292034PubMedGoogle Scholar
  54. Foulkes, WD 2004BRCA1 functions as a breast stem cell regulatorJ Med Genet4115PubMedGoogle Scholar
  55. Dobrzycka, KM, Townson, SM, Jiang, S, Oesterreich, S 2003Estrogen receptor corepressors–a role in human breast cancerEndocr Relat Cancer10517536PubMedGoogle Scholar
  56. Liehr, JG 2000Is estradiol a genotoxic mutagenic carcinogenEndocr Rev214054PubMedGoogle Scholar
  57. Yue, W, Santen, RJ, Wang, JP, Li, Y, Verderame, MF, Bocchinfuso, WP, Korach, KS, Devanesan, P, Todorovic, R, Rogan, EG, Cavalieri, EL 2003Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesisJ Steroid Biochem Mol Biol86477486PubMedGoogle Scholar
  58. Miller, K 2003Estrogen and DNA damage: the silent source of breast cancerJ Natl Cancer Inst95100102CrossRefPubMedGoogle Scholar
  59. Mobley, JA, Brueggemeier, RW 2004Estrogen receptor-mediated regulation of oxidative stress and DNA damage in breast cancerCarcinogenesis2539PubMedGoogle Scholar
  60. Hilakivi-Clarke, L 2000Estrogens, BRCA1, and breast cancerCancer Res6049935001PubMedGoogle Scholar
  61. Andersen, AA, Panning, B 2003Epigenetic gene regulation by noncoding RNAsCurr Opin Cell Biol15281289PubMedGoogle Scholar
  62. Ganesan, S, Silver, DP, Greenberg, RA, Avni, D, Drapkin, R, Miron, A, Mok, SC, Randrianarison, V, Brodie, S, Salstrom, J, Rasmussen, TP, Klimke, A, Marrese, C, Marahrens, Y, Deng, CX, Feunteun, J, Livingston, DM 2002BRCA1 supports XIST RNA concentration on the inactive X chromosomeCell111393405CrossRefPubMedGoogle Scholar
  63. Antoniou, A, Pharoah, PD, Narod, S, Risch, HA, Eyfjord, JE, Hopper, JL, Loman, N, Olsson, H, Johannsson, O, Borg, A, Pasini, B, Radice, P, Manoukian, S, Eccles, DM, Tang, N, Olah, E, Anton-Culver, H, Warner, E, Lubinski, J, Gronwald, J, Gorski, B, Tulinius, H, Thorlacius, S, Eerola, H, Nevanlinna, H, Syrjakoski, K, Kallioniemi, OP, Thompson, D, Evans, C, Peto, J, Lalloo, F, Evans, DG, Easton, DF 2003Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studiesAm J Hum Genet7211171130CrossRefPubMedGoogle Scholar
  64. Liede, A, Karlan, BY, Narod, SA 2004Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literatureJ Clin Oncol22735742PubMedGoogle Scholar
  65. Anderson, WF, Althuis, MD, Brinton, LA, Devesa, SS 2004Is male breast cancer similar or different than female breast cancerBreast Cancer Res Treat837786PubMedGoogle Scholar
  66. Jernstrom, H, Lerman, C, Ghadirian, P, Lynch, HT, Weber, B, Garber, J, Daly, M, Olopade, OI, Foulkes, WD, Warner, E, Brunet, JS, Narod, SA 1999Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2Lancet35418461850CrossRefPubMedGoogle Scholar
  67. Rebbeck, TR, Levin, AM, Eisen, A, Snyder, C, Watson, P, Cannon-Albright, L, Isaacs, C, Olopade, O, Garber, JE, Godwin, AK, Daly, MB, Narod, SA, Neuhausen, SL, Lynch, HT, Weber, BL 1999Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriersJ Natl Cancer Inst9114751479PubMedGoogle Scholar
  68. Fisher, B, Costantino, JP, Wickerham, DL, Redmond, CK, Kavanah, M, Cronin, WM, Vogel, V, Robidoux, A, Dimitrov, N, Atkins, J, Daly, M, Wieand, S, Tan-Chiu, E, Ford, L, Wolmark, N 1998Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 StudyJ Natl Cancer Inst9013711388CrossRefPubMedGoogle Scholar
  69. Early Breast Cancer Trialists’ Collaborative Group1992Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 womenLancet339115Google Scholar
  70. Narod, SA, Brunet, JS, Ghadirian, P, Robson, M, Heimdal, K, Neuhausen, SL, Stoppa-Lyonnet, D, Lerman, C, Pasini, B, los, RP, Weber, B, Lynch, H 2000Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control studyHereditary Breast Cancer Clinical Study Group. Lancet35618761881Google Scholar
  71. Metcalfe, K, Lynch, HT, Ghadirian, P, Tung, N, Olivotto, I, Warner, E, Olopade, OI, Eisen, A, Weber, B, McLennan, J, Sun, P, Foulkes, WD, Narod, SA 2004Contralateral breast cancer in BRCA1 and BRCA2 mutation carriersJ Clin Oncol2223282335PubMedGoogle Scholar
  72. Palmieri, C 2000Prognostic significance of oestrogen receptor beta in breast cancerBr J Surg8712481249PubMedGoogle Scholar
  73. Dowsett, M, Ashworth, A 2003New biology of the oestrogen receptorLancet362260262PubMedGoogle Scholar
  74. Hall, JM, McDonnell, DP 1999The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogensEndocrinology14055665578PubMedGoogle Scholar
  75. Mann, S, Laucirica, R, Carlson, N, Younes, PS, Ali, N, Younes, A, Li, Y, Younes, M 2001Estrogen receptor beta expression in invasive breast cancerHum Pathol32113118PubMedGoogle Scholar
  76. Daidone, MG, Veneroni, S, Cappelletti, V, Radice, P, Pierotti, MA, Younes, M 2002Estrogen receptor-beta expression in hereditary breast cancerJ Clin Oncol2037523753PubMedGoogle Scholar
  77. Yang, SH, Liu, R, Perez, EJ, Wen, Y, Stevens, SM,Jr., Valencia, T, Brun-Zinkernagel, AM, Prokai, L, Will, Y, Dykens, J, Koulen, P, Simpkins, JW 2004Mitochondrial localization of estrogen receptor betaProc Natl Acad Sci USA10141304135CrossRefPubMedGoogle Scholar
  78. Wang, J, Green, PS, Simpkins, JW 2001Estradiol protects against ATP depletion, mitochondrial membrane potential decline and the generation of reactive oxygen species induced by 3-nitroproprionic acid in SK-N-SH human neuroblastoma cellsJ Neurochem77804811PubMedGoogle Scholar
  79. Chan, HM, La Thangue, NB 2001p300/CBP proteins: HATs for transcriptional bridges and scaffoldsJ Cell Sci11423632373PubMedGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  1. 1.Laboratoire Jean-Claude Heuson de Cancérologie Mammaire, Institut Jules BordetUniversité Libre de BruxellesBruxellesBelgium

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