title: Deregulated estrogen receptor alpha and p53 heterozygosity collaborate in the development of mammary hyperplasia.
abstract: Both increased estrogen receptor alpha (ER(alpha)) expression and germline disruption of one p53 allele increase breast cancer risk in women. Genetically engineered mouse models of deregulated ER(alpha) expression and p53 haploinsufficiency were used to investigate similarities and differences of each genetic lesion alone and in combination on mammary preneoplasia development. Each genetic lesion independently and in combination led to development of age-dependent preneoplasia, but the highest prevalence was found in compound mice with increased ER(alpha) expression coupled with p53 heterozygosity. All genetic lesions were associated with extracellular signal-regulated kinase 1/2 activation; however, only p53 heterozygous and compound mice showed increased levels of phosphorylated AKT and decreased p27 expression. The highest levels of cell proliferation were found in compound mice, but increased levels were also found with either increased ER(alpha) expression or p53 heterozygosity. Mice with increased ER(alpha) expression showed predicted higher levels of nuclear-localized ER(alpha), but this was attenuated in compound mice in association with a relative increase in Src phosphorylation. Parity protection was limited to p53 heterozygous mice and not found in mice with increased ER(alpha) alone. In summary, increased and deregulated ER(alpha) collaborates with p53 heterozygosity in increasing the risk of mammary preneoplasia development.
authors.affiliation: Departments of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia 20057, USA.
authors.forename: Edgar S
authors.initials: ES
authors.lastname: Díaz-Cruz
authors.forename: Priscilla A
authors.initials: PA
authors.lastname: Furth
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006579:Heterozygote; D007124:Immunoenzyme Techniques; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010298:Parity; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53
references.citation: Mod Pathol. 2005 Jan;18(1):26-35
references.pmid: 15332092
references.citation: J Natl Cancer Inst. 1998 Sep 2;90(17):1262-9
references.pmid: 9731732
references.citation: Mamm Genome. 2007 May;18(5):300-9
references.pmid: 17557176
references.citation: J Natl Cancer Inst. 1998 Jan 7;90(1):37-42
references.pmid: 9428781
references.citation: N Engl J Med. 1992 Jul 30;327(5):319-28
references.pmid: 1620171
references.citation: Am J Surg. 2007 Oct;194(4):504-6
references.pmid: 17826066
references.citation: Oncogene. 1991 Mar;6(3):413-21
references.pmid: 2011397
references.citation: Cancer Res. 2003 Mar 1;63(5):1067-72
references.pmid: 12615724
references.citation: CA Cancer J Clin. 1991 May-Jun;41(3):146-65
references.pmid: 1902137
references.citation: Cell Mol Life Sci. 2008 Oct;65(20):3255-64
references.pmid: 18636226
references.citation: Cancer Res. 2003 Oct 1;63(19):6140-3
references.pmid: 14559792
references.citation: Curr Biol. 1994 Jan 1;4(1):1-7
references.pmid: 7922305
references.citation: Science. 1990 Nov 30;250(4985):1233-8
references.pmid: 1978757
references.citation: J Pathol. 1999 Feb;187(3):272-8
references.pmid: 10398078
references.citation: J Clin Invest. 2007 Aug;117(8):2205-15
references.pmid: 17627304
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12379-84
references.pmid: 11606748
references.citation: Breast Cancer Res. 2008;10(3):R43
references.pmid: 18471300
references.citation: Breast. 2007 Dec;16(6):597-605
references.pmid: 17604627
references.citation: Br J Cancer. 2001 Sep 14;85(6):869-74
references.pmid: 11556839
references.citation: Cancer Res. 2007 Jun 1;67(11):5513-21
references.pmid: 17545634
references.citation: Pathol Int. 2001 Feb;51(2):94-9
references.pmid: 11169147
references.citation: Cell Growth Differ. 1997 Aug;8(8):829-38
references.pmid: 9269892
references.citation: Am J Pathol. 2003 Nov;163(5):1713-9
references.pmid: 14578170
references.citation: Oncogene. 2009 Aug 13;28(32):2894-902
references.pmid: 19503094
references.citation: Biochim Biophys Acta. 2007 Aug;1773(8):1263-84
references.pmid: 17126425
references.citation: Eur J Cancer. 1997 Jan;33(1):39-44
references.pmid: 9071897
references.citation: J Clin Oncol. 2003 Jan 1;21(1):28-34
references.pmid: 12506166
references.citation: J Surg Res. 2007 Jun 1;140(1):109-14
references.pmid: 17291532
references.citation: J Pathol. 2001 Jul;194(3):327-33
references.pmid: 11439365
references.citation: FASEB J. 2002 Mar;16(3):283-92
references.pmid: 11874978
references.citation: Steroids. 2009 Jul;74(7):622-7
references.pmid: 18996136
references.citation: Cell. 2007 Jan 26;128(2):281-94
references.pmid: 17254967
references.citation: Cancer Res. 2005 Feb 1;65(3):681-5
references.pmid: 15705859
references.citation: Transgenic Res. 2002 Aug;11(4):361-72
references.pmid: 12212839
references.citation: J Mammary Gland Biol Neoplasia. 2002 Jan;7(1):3-15
references.pmid: 12160084
references.citation: Science. 1994 Nov 4;266(5186):807-10
references.pmid: 7973635
references.citation: Cell Mol Life Sci. 1999 Jan;55(1):48-63
references.pmid: 10065151
references.citation: J Cell Physiol. 2000 Apr;183(1):10-7
references.pmid: 10699961
references.citation: Hum Pathol. 1997 Aug;28(8):974-9
references.pmid: 9269835
references.citation: Breast Cancer Res Treat. 1994;32(1):39-47
references.pmid: 7819584
references.citation: Cancer Res. 2009 Apr 15;69(8):3405-14
references.pmid: 19351845
references.citation: Mol Cell Biol. 2009 Jun;29(11):3088-98
references.pmid: 19349302
references.citation: Br J Cancer. 1997;76(1):1-14
references.pmid: 9218725
references.citation: Cancer Res. 1994 Sep 15;54(18):4855-78
references.pmid: 8069852
references.citation: FASEB J. 2002 Jun;16(8):881-3
references.pmid: 11967232
references.citation: J Natl Cancer Inst. 2007 Aug 1;99(15):1152-61
references.pmid: 17652280
references.citation: Breast Cancer Res. 2002;4(2):70-6
references.pmid: 11879567
references.citation: Endocr Relat Cancer. 2006 Jun;13(2):293-325
references.pmid: 16728565
references.citation: Br J Biomed Sci. 2004;61(2):99-102
references.pmid: 15250676
references.citation: Cancer Res. 1987 Nov 1;47(21):5748-51
references.pmid: 3664479