title: Amyloid precursor protein in human breast cancer: an androgen-induced gene associated with cell proliferation.
abstract: Amyloid precursor protein (APP) is a transmembrane protein that is highly expressed in brain tissue. Recently, APP has been implicated in some human malignancies, and its regulation by androgens has also been demonstrated. Such findings suggest the importance of APP in hormone-dependent breast carcinoma, but APP has not yet been examined in breast carcinoma tissues. Therefore, in this study, we examined the biological and clinical significance of APP in breast carcinoma using immunohistochemistry and in vitro studies. APP immunoreactivity was detected in 57 out of 117 (49%) breast carcinoma tissues examined, and it was positively associated with androgen receptor (AR) expression. APP immunoreactivity was also significantly associated with Ki-67 LI and increased risk of recurrence in the estrogen receptor (ER)-positive cases, and was an independent prognostic factor in these patients. Subsequent in vitro experiments demonstrated that APP mRNA expression was significantly induced by biologically active androgen dihydrotestosterone in both a dose-dependent and a time-dependent manner in MCF-7 breast carcinoma cells, which was potently suppressed by an AR blocker hydroxyflutamide. Moreover, cell proliferation activity of MCF-7 and MDA-MB-231 cells was significantly associated with their APP expression level. These findings suggest that APP is an androgen-induced gene that promotes proliferation activity of breast carcinoma cells. Moreover, APP immunohistochemical status is considered a potent prognostic factor in ER-positive breast cancer patients.
authors.affiliation: Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takagi
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ito
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Miki
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Shibahara
authors.forename: Takanori
authors.initials: T
authors.lastname: Ishida
authors.forename: Mika
authors.initials: M
authors.lastname: Watanabe
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000728:Androgens / Q000494:pharmacology / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D013196:Dihydrotestosterone / Q000494:pharmacology; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D008875:Middle Aged; D011379:Prognosis; D011944:Receptors, Androgen / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D000728:Androgens; D011944:Receptors, Androgen; D013196:Dihydrotestosterone
references.citation: J Biol Chem. 1994 May 6;269(18):13065-8
references.pmid: 8175728
references.citation: Int J Cancer. 1991 Sep 30;49(3):436-43
references.pmid: 1917142
references.citation: Nat Rev Neurosci. 2007 Jul;8(7):499-509
references.pmid: 17551515
references.citation: Eur J Surg Oncol. 1992 Apr;18(2):112-8
references.pmid: 1582503
references.citation: Br J Cancer. 2007 May 21;96(10):1504-13
references.pmid: 17453008
references.citation: Oncol Rep. 2004 Oct;12(4):709-16
references.pmid: 15375489
references.citation: J Steroid Biochem Mol Biol. 1995 May;52(5):459-67
references.pmid: 7748811
references.citation: Biochem Biophys Res Commun. 2012 Aug 17;425(1):76-82
references.pmid: 22820195
references.citation: Oncol Lett. 2012 Jun;3(6):1227-1230
references.pmid: 22783423
references.citation: Exp Mol Med. 2012 May 31;44(5):330-9
references.pmid: 22314197
references.citation: Steroids. 1975 Dec;26(6):785-95
references.pmid: 175527
references.citation: Cancer Res. 1991 Jun 1;51(11):2797-802
references.pmid: 2032219
references.citation: J Clin Pathol. 2004 Jul;57(7):675-81
references.pmid: 15220356
references.citation: Int J Cancer. 2001 Apr 1;92(1):31-9
references.pmid: 11279603
references.citation: Int J Cancer. 2004 Sep 20;111(5):727-32
references.pmid: 15252842
references.citation: Neoplasia. 2008 Jun;10(6):542-8
references.pmid: 18516291
references.citation: J Pathol. 1993 May;170(1):31-5
references.pmid: 8100853
references.citation: Cancer Sci. 2012 Jan;103(1):136-43
references.pmid: 21988594
references.citation: J Clin Endocrinol Metab. 2001 May;86(5):2250-7
references.pmid: 11344235
references.citation: Endocr Relat Cancer. 2010 Apr 21;17(2):415-30
references.pmid: 20228125
references.citation: Ann Oncol. 2011 Aug;22(8):1736-47
references.pmid: 21709140
references.citation: Cancer Res. 2003 Nov 1;63(21):7032-7
references.pmid: 14612490
references.citation: J Endocrinol. 2008 Aug;198(2):291-9
references.pmid: 18480379
references.citation: Cancer Sci. 2013 Nov;104(11):1532-8
references.pmid: 23889773
references.citation: J Neuropathol Exp Neurol. 1993 Jan;52(1):22-30
references.pmid: 7678853
references.citation: Nat Struct Biol. 1999 Apr;6(4):327-31
references.pmid: 10201399
references.citation: Endocr Relat Cancer. 2012 Nov 06;19(6):741-50
references.pmid: 22936544
references.citation: Cancer Res. 2004 Oct 15;64(20):7405-11
references.pmid: 15492263
references.citation: Cancer Res. 2009 Jan 1;69(1):137-42
references.pmid: 19117996
references.citation: Eur J Pharmacol. 2000 Sep 29;405(1-3):277-83
references.pmid: 11033334
references.citation: Oncogene. 2006 Jun 29;25(28):3994-4008
references.pmid: 16491124
references.citation: Breast Cancer Res Treat. 1988 Oct;12(2):213-25
references.pmid: 3242650