Cyclin D1 splice variants: polymorphism, risk, and isoform-specific regulation in prostate cancer.
OBJECTIVE
Alternative CCND1 splicing results in cyclin D1b, which has specialized, protumorigenic functions in prostate not shared by the cyclin D1a (full length) isoform. Here, the frequency, tumor relevance, and mechanisms controlling cyclin D1b were challenged.


METHODS
First, relative expression of both cyclin D1 isoforms was determined in prostate adenocarcinomas. Second, relevance of the androgen axis was determined. Third, minigenes were created to interrogate the role of the G/A870 polymorphism (within the splice site), and findings were validated in primary tissue. Fourth, the effect of G/A870 on cancer risk was assessed in two large case-control studies.


RESULTS
Cyclin D1b is induced in tumors, and a significant subset expressed this isoform in the absence of detectable cyclin D1a. Accordingly, the isoforms showed noncorrelated expression patterns, and hormone status did not alter splicing. Whereas G/A870 was not independently predictive of cancer risk, A870 predisposed for transcript-b production in cells and in normal prostate. The influence of A870 on overall transcript-b levels was relieved in tumors, indicating that aberrations in tumorigenesis likely alter the influence of the polymorphism.


CONCLUSIONS
These studies reveal that cyclin D1b is specifically elevated in prostate tumorigenesis. Cyclin D1b expression patterns are distinct from that observed with cyclin D1a. The A870 allele predisposes for transcript-b production in a context-specific manner. Although A870 does not independently predict cancer risk, tumor cells can bypass the influence of the polymorphism. These findings have major implications for the analyses of D-cyclin function in the prostate and provide the foundation for future studies directed at identifying potential modifiers of the G/A870 polymorphism.
Comstock
Clay E S
CE
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Augello
Michael A
MA
Benito
Ruth Pe
RP
Karch
Jason
J
Tran
Thai H
TH
Utama
Fransiscus E
FE
Tindall
Elizabeth A
EA
Wang
Ying
Y
Burd
Craig J
CJ
Groh
Eric M
EM
Hoang
Hoa N
HN
Giles
Graham G
GG
Severi
Gianluca
G
Hayes
Vanessa M
VM
Henderson
Brian E
BE
Le Marchand
Loic
L
Kolonel
Laurence N
LN
Haiman
Christopher A
CA
Baffa
Raffaele
R
Gomella
Leonard G
LG
Knudsen
Erik S
ES
Rui
Hallgeir
H
Henshall
Susan M
SM
Sutherland
Robert L
RL
Knudsen
Karen E
KE
D000483:Alleles; D017398:Alternative Splicing / Q000235:genetics*; D016022:Case-Control Studies; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis
D020033:Protein Isoforms; D019938:Cyclin D1
Cancer Res. 2008 Jul 15;68(14):5628-38
18632615
J Biol Chem. 2003 Aug 8;278(32):30339-47
12746453
Exp Biol Med (Maywood). 2006 Jul;231(7):1271-81
16816134
Cancer Lett. 1995 Jul 13;93(2):165-70
7621424
Cancer Res. 2006 Aug 1;66(15):7783-92
16885382
Breast Cancer Res Treat. 2008 Jan;107(1):95-102
18043898
Oncogene. 2006 Mar 13;25(11):1620-8
16550162
Cell Cycle. 2008 Aug;7(15):2299-305
18677114
Biochem Biophys Res Commun. 1990 Dec 14;173(2):534-40
2260966
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2190-5
16461912
Oncogene. 2003 Nov 27;22(54):8723-30
14647467
Am J Pathol. 2004 Mar;164(3):831-40
14982837
Nucleic Acids Res. 2002 May 1;30(9):e36
11972351
Eur J Cancer. 2005 May;41(7):1037-44
15862753
Carcinogenesis. 2002 Feb;23(2):257-64
11872630
J Cancer Res Clin Oncol. 2005 Jul;131(7):479-85
15809880
Br J Cancer. 1997;75(12):1761-8
9192978
Cancer Res. 2009 Jan 1;69(1):16-22
19117982
Nucl Recept Signal. 2008 Feb 01;6:e001
18301781
J Clin Oncol. 2003 Jun 1;21(11):2085-93
12775733
J Cell Biochem. 2006 Oct 1;99(2):373-81
16598769
Oncogene. 2006 Feb 16;25(7):998-1007
16247460
J Biol Chem. 2007 Jan 26;282(4):2278-87
17148459
Proc Natl Acad Sci U S A. 2008 Apr 22;105(16):6004-9
18413612
Cancer Res. 2009 Mar 15;69(6):2305-13
19244107
Cancer Res. 2008 Sep 15;68(18):7621-8
18794151
Cell Cycle. 2006 Sep;5(18):2110-4
16969111
Oncogene. 1998 Apr 2;16(13):1701-12
9582018
Oncol Rep. 2003 Sep-Oct;10(5):1615-23
12883749
Urology. 2002 Sep;60(3 Suppl 1):132-8; discussion 138-9
12231070
Nat Rev Cancer. 2008 Jul;8(7):497-511
18563191
Int J Cancer. 2003 Jan 1;103(1):116-20
12455063
Curr Opin Urol. 2006 May;16(3):123-31
16679847
Nat Struct Mol Biol. 2006 Jan;13(1):22-9
16341228
Oncogene. 2009 Apr 16;28(15):1812-20
19287456
Pathol Res Pract. 1996 Jul;192(7):752-60
8880876
Br J Cancer. 2007 Mar 26;96(6):970-9
17375037
Am J Pathol. 2001 Nov;159(5):1917-24
11696452
Mol Cell Biol. 1995 May;15(5):2600-11
7739541
Mol Carcinog. 2006 Dec;45(12):901-13
17013836
Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11217-22
10500157
Mol Cancer Ther. 2002 May;1(7):515-24
12479269
Nat Rev Cancer. 2008 Sep;8(9):714-24
19143056
Mol Cell Biol. 2003 Nov;23(21):7719-31
14560017
Cancer Res. 2003 Nov 1;63(21):7056-61
14612495
Am J Epidemiol. 2000 Feb 15;151(4):346-57
10695593
Anticancer Res. 2003 Nov-Dec;23(6D):4947-51
14981950
Cancer Res. 2001 Aug 15;61(16):6042-5
11507050
Hum Pathol. 2008 Dec;39(12):1792-801
18715616
Oral Oncol. 2008 Jul;44(7):689-97
18061526
Mol Cell Biol. 2005 Mar;25(6):2200-15
15743818
Oncogene. 2006 Oct 12;25(47):6291-303
16732330
Cell Div. 2006 Jul 24;1:15
16863592
Cell Cycle. 2007 Jun 1;6(11):1307-13
17568191
Int J Cancer. 2002 Mar 20;98(3):415-8
11920593
Cancer Res. 2008 Jul 1;68(13):5469-77
18593950
Cancer Res. 2008 Dec 15;68(24):10154-62
19074882
J Clin Pathol. 2008 Aug;61(8):920-7
18552173
Oncogene. 1995 Sep 7;11(5):1005-11
7675441
Int J Cancer. 2005 Apr 10;114(3):364-70
15551329
Cancer Res. 2008 Dec 1;68(23):9918-27
19047173
Br J Cancer. 2008 Sep 16;99(6):847-51
18781147
J Natl Cancer Inst. 2006 Oct 4;98(19):1420-4
17018789
Genes Dev. 2004 Nov 15;18(22):2699-711
15545627
Exp Cell Res. 2007 Jul 15;313(12):2719-29
17499716
J Cell Biol. 1994 May;125(3):625-38
8175885
Genes Dev. 2006 Sep 15;20(18):2513-26
16980581
Blood. 2006 Sep 1;108(5):1744-50
16690963
Cancer Epidemiol Biomarkers Prev. 2008 Oct;17(10):2773-81
18843022
Int J Cancer. 1994 May 1;57(3):353-61
8168995
J Natl Cancer Inst. 2003 Jun 4;95(11):818-24
12783937