Advertisement

BRCA1 in initiation, invasion, and metastasis of breast cancer: a perspective from the tumor microenvironment

  • Shaun D. McCullough
  • Yanfen Hu
  • Rong Li
Part of the Cancer Metastasis – Biology and Treatment book series (CMBT, volume 11)

Abstract

Women who inherit cancer-predisposing mutations in the BRCA1 gene have about 80% lifetime chance of developing breast cancer. BRCA1 mutation-associated tumors are often diagnosed as high-grade, typically display a basal epithelial phenotype, and proliferate rapidly. While somatic mutations of BRCA1 are rarely found in sporadic breast cancer cases, 30– 40% of the sporadic cases show reduced BRCA1 expression, supporting the notion that impaired BRCA1 function may contribute to the development of both familial and sporadic forms of breast cancer. Furthermore, low levels of BRCA1 expression have been linked with the occurrence of distant metastases in sporadic disease. Since cloning of the gene more than a decade ago, BRCA1 has been implicated in a large array of cellular functions, most notably DNA damage repair. However, the relationship between the known molecular functions of BRCA1 and the clinicopathological features of BRCA1-associated tumors remains elusive. Why do BRCA1 mutations predominantly affect female breast and ovaries? Why do BRCA1-associated cancers tend to have a poor prognosis? How can the knowledge of BRCA1 function be translated into more targeted and efficacious therapies? In this review, we will discuss these important issues in light of some recent findings from laboratory and preclinical studies, which point to a need to look “outside the box” of epithelial cells by elucidating BRCA1 functions in the context of the unique tumor microenvironment.

Keywords

BRCA1 DNA repair transcription estrogen tissue-specificity estrogen receptor tumor microenvironment 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Friedman LS et al. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet, 1994; 8: 399-404.PubMedCrossRefGoogle Scholar
  2. 2.
    Miki Y et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science, 1994; 266(5182): 66-71.PubMedCrossRefGoogle Scholar
  3. 3.
    Rahman N and MR. Stratton. The genetics of breast cancer susceptibility. Annu Rev Genet, 1998; 32: 95-121.PubMedCrossRefGoogle Scholar
  4. 4.
    Welcsh PL and M-C King. BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Genet, 2001; 10: 705-713.PubMedCrossRefGoogle Scholar
  5. 5.
    Nathanson KL, R Wooster, and BL Weber. Breast cancer genetics: what we know and what we need. Nat Med, 2001; 7: 552-556.PubMedCrossRefGoogle Scholar
  6. 6.
    Narod SA and WD Foulkes. BRCA1 and BRCA2: 1994 and beyond. Nature Reviews Cancer, 2004; 4: 665-676.PubMedCrossRefGoogle Scholar
  7. 7.
    Rosen EM et al. BRCA1 gene in breast cancer. J Cell Physiol, 2003; 196: 19-41.PubMedCrossRefGoogle Scholar
  8. 8.
    Thompson ME et al. Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet, 1995; 9: 444-450.PubMedCrossRefGoogle Scholar
  9. 9.
    Magdinier F et al. Regional methylation of the 5’ end CpG island of BRCA1 is associated with reduced gene expression in human somatic cells. FASEB J, 2000; 14: 1585-1594.PubMedCrossRefGoogle Scholar
  10. 10.
    Catteau A et al. Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer: correlation with disease characteristics. Oncogene, 1999; 18: 1957-1965.PubMedCrossRefGoogle Scholar
  11. 11.
    Esteller M et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst, 2000; 5: 564-569.CrossRefGoogle Scholar
  12. 12.
    King MC, Marks JH, and Mandell JB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science, 2003; 302(5645): 643-646.PubMedCrossRefGoogle Scholar
  13. 13.
    Scully R and DM Livingston. In search of the tumor-suppressor functions of BRCA1 and BRCA2. Nature, 2000; 408: 429-432.PubMedCrossRefGoogle Scholar
  14. 14.
    Zheng L et al. Lessons learned from BRCA1 and BRCA2. Oncogene, 2000; 19(53): 159-175.Google Scholar
  15. 15.
    Monteiro ANA. BRCA1: exploring the links to transcription. TIBS, 2000; 25: 469-474.PubMedGoogle Scholar
  16. 16.
    Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell, 2002; 108: 171-182.PubMedCrossRefGoogle Scholar
  17. 17.
    Deng CX. Role of BRCA1 in centrosome duplication. Oncogene, 2002; 21: 6222-6227.PubMedCrossRefGoogle Scholar
  18. 18.
    Jasin M. Homologous repair of DNA damage and tumorigenesis: The BRCA connection. Oncogene, 2002; 21: 8981-8993.Google Scholar
  19. 19.
    Baer R. and T Ludwig. The BRCA1/BARD1 heterodimer, a tumor suppressor complex with ubiquitin E3 ligase activity. Curr Opin Genet Dev, 2002; 12: 86-91.PubMedCrossRefGoogle Scholar
  20. 20.
    Starita LM, and JD Parvin. The multiple nuclear functions of BRCA1: transcription, ubiquitination and DNA repair. Curr Opin Cell Biol, 2003; 15: 345-350.PubMedCrossRefGoogle Scholar
  21. 21.
    Lane TF. BRCA1 and transcription. Cancer Biol. and Ther, 2004; 3: 75-80.Google Scholar
  22. 22.
    Paull TT et al. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol, 2000; 10: 886-895.PubMedCrossRefGoogle Scholar
  23. 23.
    Scully R et al. Dynamic changes of BRCA1 subnuclear location and phos-phorylation state are initiated by DNA damage. Cell, 1997; 90: 425-435.PubMedCrossRefGoogle Scholar
  24. 24.
    Zhong Q et al. Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response. Science, 1999. 285: 747-750.PubMedCrossRefGoogle Scholar
  25. 25.
    Dong Y et al. Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Mol. Cell, 2003; 12: 1087-1099.PubMedCrossRefGoogle Scholar
  26. 26.
    Wang Y et al. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes & Dev, 2000; 14: 927-939.Google Scholar
  27. 27.
    Cortez D et al. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science, 1999; 286(5442): 1162-1166.PubMedCrossRefGoogle Scholar
  28. 28.
    Tibbetts RS et al. Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes & Dev, 2000; 14: 2989-3002.CrossRefGoogle Scholar
  29. 29.
    Lee J-S et al. HCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature, 2000; 404: 201-204.PubMedCrossRefGoogle Scholar
  30. 30.
    Moynahan ME et al. Brca1 controls homology-directed DNA repair. Mol Cell, 1999; 4(4): 511-518.PubMedCrossRefGoogle Scholar
  31. 31.
    Abbott DW et al. BRCA1 expression restores radiation resistance in BRCA1-defective cancer cells through enhancement of transcription-coupled DNA repair. J Biol Chem, 1999; 274(26): 18808-18812.PubMedCrossRefGoogle Scholar
  32. 32.
    Moynahan ME, Cui TY, and Jasin M. Homology-directed DNA repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res, 2001; 61: 4842-4850.PubMedGoogle Scholar
  33. 33.
    Wang H et al. Nonhomologous end-joining of ionizing radiation-induced DNA doulbe-stranded breaks in human tumor cells deficient in BRCA1 and BRCA2. Cancer Res., 2001; 61: 270-277.PubMedGoogle Scholar
  34. 34.
    Zhong Q et al. Deficient nonhomologous end-joining activity in cell-free extracts from brca1-null fibroblasts. Cancer Res, 2002; 62: 3966-3970.PubMedGoogle Scholar
  35. 35.
    Zhang H et al. BRCA1 physically associated with p53 and stimulates its transcriptional activity. Oncogene, 1998; 16: 1713-1721.PubMedCrossRefGoogle Scholar
  36. 36.
    Ongusaha PP et al. BRCA1 shifts p53-mediated cellular outcomes towards irreversible growth arrest. Oncogene, 2003; 22: 3749-3758.PubMedCrossRefGoogle Scholar
  37. 37.
    Ouchi T et al. Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-gamma target genes. Proc Natl Acad Sci USA, 2000; 97(10): 5208-5213.PubMedCrossRefGoogle Scholar
  38. 38.
    Houvras Y et al. BRCA1 physically and functionally interacts with ATF1. J Biol Chem, 2000; 275(46): 36230-36237.PubMedCrossRefGoogle Scholar
  39. 39.
    Zheng L et al. Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1. Mol. Cell, 2000; 6: 757-768.CrossRefGoogle Scholar
  40. 40.
    Fan S et al. Role of direct interaction in BRCA1 inhibition of estrogen receptor activity. Oncogene, 2001; 20(1): 77-87.PubMedCrossRefGoogle Scholar
  41. 41.
    Hu Y-F. and Li R. JunB Potentiates function of BRCA1 Activation Domain 1(AD1) through a coiled-coil-mediated interaction. Genes & Dev, 2002; 16: 1509-1517.CrossRefGoogle Scholar
  42. 42.
    Neish AS et al. Factors associated with the mammalian RNA polymerase II holoenzyme. Nucleic Acids Res, 1998; 26(3): 847-53.PubMedCrossRefGoogle Scholar
  43. 43.
    Yarden RI and Brody LC. BRCA1 interacts with components of the histone deacetylase complex. Proc Natl Acad Sci USA, 1999; 96(9): 4983-4988.PubMedCrossRefGoogle Scholar
  44. 44.
    Pao GM et al. CBP/p300 interact with and function as transcriptional coactivators of BRCA1. Proc Natl Acad Sci USA, 2000; 97(3): 1020-1025.PubMedCrossRefGoogle Scholar
  45. 45.
    Bochar DA et al. BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell, 2000; 102: 257-265.PubMedCrossRefGoogle Scholar
  46. 46.
    Scully R et al. BRCA1 is a component of the RNA polymerase II holoenzyme. Proc Natl Acad Sci USA, 1997; 94(11): 5605-5610.PubMedCrossRefGoogle Scholar
  47. 47.
    Anderson SF et al. BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A. Nat Genet, 1998; 19: 254-256.PubMedCrossRefGoogle Scholar
  48. 48.
    Krum SA et al. BRCA1 associates with processive RNA polymerase II. J Biol Chem, 2003; 278: 52012-52020.Google Scholar
  49. 49.
    Somasundaram K et al. Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1. Nature, 1997; 389(6647): 187-190.PubMedGoogle Scholar
  50. 50.
    Ouchi T et al. BRCA1 regulates p53-dependent gene expression. Proc Natl Acad Sci USA, 1998; 95(5): 2302-2306.PubMedCrossRefGoogle Scholar
  51. 51.
    Harkin DP et al. Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell, 1999; 97: 575-586.PubMedCrossRefGoogle Scholar
  52. 52.
    MacLachlan TK et al. BRCA1 effects on the cell cycle and DNA damage response are linked to altered gene expression. J Biol Chem, 2000; 275: 2777-2785.PubMedCrossRefGoogle Scholar
  53. 53.
    Aprelikova O et al. BRCA1 is a selective coactivator of 14-3-3s gene transcription in mouse embryonic stem cells. J Biol Chem, 2001; 276: 25647-25650.PubMedCrossRefGoogle Scholar
  54. 54.
    Wang RH, Yu H, and Deng CX. A requirement for breast-cancer-associated gene 1 (BRCA1) in the spindle checkpoint. Proc Natl Acad Sci USA, 2004; 101: 17108-17113.PubMedCrossRefGoogle Scholar
  55. 55.
    Zheng L et al. BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor. Proc Natl Acad Sci USA, 2001; 98: 9587-9592.PubMedCrossRefGoogle Scholar
  56. 56.
    Furuta S et al. Removal of BRCA1/CtIP/ZBRK1 repressor complex on ANG1 promoter leads to accelerated mammary tumor growth contributed by prominent vasculature. Cancer Cell, 2006; 10: 13-24.PubMedCrossRefGoogle Scholar
  57. 57.
    Ohta T and Fukuda M. Ubiquitin and breast cancer. Oncogene, 2004; 23: 2079-2088.PubMedCrossRefGoogle Scholar
  58. 58.
    Kleiman FE et al. BRCA1/BARD1 inhibition of mRNA 3’ processing involves targeted degradation of RNA polymerase II. Genes Dev, 2005; 15: 1227-1237.CrossRefGoogle Scholar
  59. 59.
    Starita LM et al. BRCA1/BARD1 ubiquitinate phosphorylated RNA polymerase II. J Biol Chem, 2005; 280: 24498-24505.PubMedCrossRefGoogle Scholar
  60. 60.
    Starita LM et al. BRCA1-dependent ubiquitination of gamma-tubulin regulates centrosome number. Mol Cell Biol, 2004; 24: 8457-8466.PubMedCrossRefGoogle Scholar
  61. 61.
    Hakem R et al. The Tumor Suppressor Gene Brca1 Is Required for Embryonic Cellular Proliferation in the Mouse. Cell, 1996; 85: 1009-1023.PubMedCrossRefGoogle Scholar
  62. 62.
    Hakem R et al. Partial rescue of Brca1 (5-6) early embryonic lethality by p53 or p21 null mutation. Nat Genet, 1997; 16: 298-302.PubMedCrossRefGoogle Scholar
  63. 63.
    Cao L et al. ATM-Chk2-p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency. EMBO J, 2006; 25: 2167-2177.PubMedCrossRefGoogle Scholar
  64. 64.
    Schuyer M and Berns EM. Is TP53 dysfunction required for BRCA1- associated carcinogenesis? Mol Cell Endocrinol, 1999; 155: 143-152.PubMedCrossRefGoogle Scholar
  65. 65.
    Elledge SJ and Amon A. The BRCA1 suppressor hypothesis: an explanation for the tissue-specific tumor development in BRCA1 patients. Cancer Cell, 2002; 1: 129-132.PubMedCrossRefGoogle Scholar
  66. 66.
    Monteiro ANA. BRCA1: the enigma of tissue-specific tumor development. Trends Genet, 2003; 19: 312-315.PubMedCrossRefGoogle Scholar
  67. 67.
    Hennighausen L and GW Robinson. Think globally, act locally: the making of a mouse mammary gland. Genes & Dev, 1998; 12: 449-455.CrossRefGoogle Scholar
  68. 68.
    Nilsson S et al. Mechanisms of estrogen action. Physiol Rev, 2001; 81: 1535-1565.PubMedGoogle Scholar
  69. 69.
    Hall JM, JF Couse, and KS Korach. The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem, 2001; 276: 36869-36872.PubMedCrossRefGoogle Scholar
  70. 70.
    Anzick SL et al. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science, 1997; 277: 965-968.PubMedCrossRefGoogle Scholar
  71. 71.
    Khan SA et al. Estrogen receptor expression in benign breast epithelium and breast cancer risk. J Natl Cancer Inst, 1998; 90: 37-42.PubMedCrossRefGoogle Scholar
  72. 72.
    Fan S et al. BRCA1 inhibition of estrogen receptor signaling in transfected cells. Science, 1999; 284(5418): 1354-1356.PubMedCrossRefGoogle Scholar
  73. 73.
    Xu J, Fan S, and Rosen EM. Regulation of the estrogen-inducible gene expression profile by the breast cancer susceptibility gene BRCA1. Endocrinology, 2005; 146: 2031-2047.PubMedCrossRefGoogle Scholar
  74. 74.
    Nass SJ and Davidson NE. Advance in Breast Cancer Therapy. Hematology/ oncology Clinics of North America, 2001; 13(2): 1-23.Google Scholar
  75. 75.
    Nilsson S and Gustafsson J-A. Basic aspects of estrogen action. Breast Cancer Res, 2000; 2: 360-366.PubMedCrossRefGoogle Scholar
  76. 76.
    Persson I. Estrogens in the causation of breast, endometrial, and ovarian cancers-evidence and hypotheses from epidemiological findings. Steroid Biochem. & Mol Biol, 2000; 74: 357-364.CrossRefGoogle Scholar
  77. 77.
    Ali S and Coombes RC. Endocrine-responsive breast cancer and strategies for combating resistance. Nature Reviews Cancer, 2002; 2: 101-112.PubMedCrossRefGoogle Scholar
  78. 78.
    Dumitrescu RG and Cotarla I. Understanding breast cancer risk - where do we stand in 2005? J Cell Mol Med, 2005; 9: 208-221.PubMedCrossRefGoogle Scholar
  79. 79.
    Wooster R and Weber BL. Breast and ovarian cancer. N Engl J Med, 2003; 348: 2339-2347.PubMedCrossRefGoogle Scholar
  80. 80.
    Simpson ER and Davis SR. Minireview: aromatase and the regulation of estrogen biosynthesis-some new perspectives. Endocrinol, 2001; 142: 4589-4594.CrossRefGoogle Scholar
  81. 81.
    Hu Y-F et al. Modulation of aromatase expression by BRCA1: a possible link to tissue-specific tumor suppression. Oncogene, 2005; 24: 8343-8348.PubMedCrossRefGoogle Scholar
  82. 82.
    Chodankar R et al. Cell-nonautonomous induction of ovarian and uterine serous cystadenomas in mice lacking a functional Brca1 in ovarian granulosa cells. Curr Biol, 2005; 15: 561-565.PubMedCrossRefGoogle Scholar
  83. 83.
    Bulun SE et al. The human CYP19 (aromatase P450) gene: update on physiologic roles and genomic organization of promoters. J Steroid Biochem Mol Biol, 2003; 86: 219-224.PubMedCrossRefGoogle Scholar
  84. 84.
    Simpson ER et al. Estrogen-the good, the bad, and the unexpected. Endocr Rev, 2005; 26: 332-330.CrossRefGoogle Scholar
  85. 85.
    Sasano H and Harada N. Intratumoral aromatase in human breast, endometrial, and ovarian malignacies. Endocrine Rev, 1998; 19: 583-607.CrossRefGoogle Scholar
  86. 86.
    Purohit A and Reed MJ. Regulation of estrogen synthesis in postmenopausal women. Steroids, 2002; 67: 979-983.PubMedCrossRefGoogle Scholar
  87. 87.
    Bulun SE et al. A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrinol Metab, 1993; 77: 1622-1628.PubMedCrossRefGoogle Scholar
  88. 88.
    Harada N. Aberrant expression of aromatase in breast cancer tissues. J Steroid Biochem Mol Biol, 1997; 61: 175-184.PubMedCrossRefGoogle Scholar
  89. 89.
    Zhao Y et al. Estrogen biosynthesis proximal to a breast tumor is stimulated by PGE2 via cyclic AMP, leading to activation of promoter II of the CYP19 (aromatase) gene. Endocrinology, 1996; 137: 5739-5742.PubMedCrossRefGoogle Scholar
  90. 90.
    Morales L, Neven and R Paridaens, Choosing between an aromatase inhibitor and tamoxifen in the adjuvant setting. Curr Opin Oncol, 2005; 17: 559-565.PubMedCrossRefGoogle Scholar
  91. 91.
    Ghosh S et al. Tumor Suppressor BRCA1 Inhibits a Breast Cancer-Associated Promoter of the Aromatase Gene (Cyp19) in Human Adipose Stromal Cells. Am J Physiol Endocrinol Metab, 2006. [Epub ahead of print].Google Scholar
  92. 92.
    Lu M et al. BRCA1 negatively regulates the cancer-associated aromatase promoters I.3 and II in breast adipose fibroblasts and malignant epithelial cells. J Clin Endocrinol Metab, 2006. [Epub ahead of print].Google Scholar
  93. 93.
    Russo J et al. Estrogen and its metabolites are carcinogenic agents in human breast epithelial cells. J Steroid Biochem Mol Biol, 2003; 87: 1-25.PubMedCrossRefGoogle Scholar
  94. 94.
    Perou CM et al. Molecular portraits of human breast tumors. Nature, 2000; 406: 747-752.PubMedCrossRefGoogle Scholar
  95. 95.
    van ’t Veer LJ et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature, 2002; 415: 530-536.PubMedCrossRefGoogle Scholar
  96. 96.
    Kauff ND et al., Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N. Engl. J. Med., 2002. 346: 1609-1615.PubMedCrossRefGoogle Scholar
  97. 97.
    Rebbeck TR et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. New Engl J Med, 2002; 346: 1616-1622.PubMedCrossRefGoogle Scholar
  98. 98.
    Bachelier R et al. Effect of bilateral oophorectomy on mammary tumor formation in BRCA1 mutant mice. Oncol Rep, 2005; 14: 1117-1120.PubMedGoogle Scholar
  99. 99.
    Narod SA et al. Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Hereditary Breast Cancer Clinical Study Grou Lancet, 2000; 356: 1876-1881.Google Scholar
  100. 100.
    Xu X et al. Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nature Genetics, 1999; 22: 37-43.PubMedCrossRefGoogle Scholar
  101. 101.
    Albiges L et al. Spectrum of breast cancer metastasis in BRCA1 mutation carriers: highly increased incidence of brain metastases. Ann Oncol., 2005; 16: 1846-1847.PubMedCrossRefGoogle Scholar
  102. 102.
    Bissell MJ and Radisky D. Putting tumors in context. Nature Reviews Cancer, 2001; 1: 46-54.PubMedCrossRefGoogle Scholar
  103. 103.
    Bissell MJ et al. The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation, 2002; 70: 537-546.PubMedCrossRefGoogle Scholar
  104. 104.
    Furuta S et al. Depletion of BRCA1 impairs differentiation but enhances proliferation of mammary epithelial cells. Proc Natl Acad Sci USA, 2005; 102: 9176-9181.PubMedCrossRefGoogle Scholar
  105. 105.
    Kawai H et al. Direct interaction between BRCA1 and the estrogen receptor regulates vascular endothelial growth factor (VEGF) transcription and secretion in breast cancer cells. Oncogene, 2002; 21: 7730-7739.PubMedCrossRefGoogle Scholar
  106. 106.
    Weber F et al. Total-genome analysis of BRCA1/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. Am J Hum Genet., 2006; 78: 961-972.PubMedCrossRefGoogle Scholar
  107. 107.
    Kiaris H et al. Evidence for nonautonomous effect of p53 tumor suppressor in carcinogenesis. Cancer Res, 2005; 65: 1627-1630.PubMedCrossRefGoogle Scholar
  108. 108.
    Hill R et al. Selective evolution of stromal mesenchyme with p53 loss in response to epithelial tumorigenesis. Cell, 2005; 123: 1001-1011.PubMedCrossRefGoogle Scholar
  109. 109.
    Jacobsen BM et al. Spontaneous fusion with, and transformation of mouse stroma by, malignant human breast cancer epithelium. Cancer Res, 2006; 66: 8274-8279.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Shaun D. McCullough
    • 1
  • Yanfen Hu
    • 2
  • Rong Li
    • 3
  1. 1.Department of Biochemistry and Molecular GeneticsSchool of Medicine University of VirginiaUSA
  2. 2.Department of Biochemistry and Molecular GeneticsSchool of Medicine University of VirginiaUSA
  3. 3.Department of Biochemistry and Molecular GeneticsSchool of Medicine University of VirginiaUSA

Personalised recommendations