The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas.
BACKGROUND
Breast cancers can be classified using whole genome expression into distinct subtypes that show differences in prognosis. One of these groups, the basal-like subtype, is poorly differentiated, highly metastatic, genomically unstable, and contains specific genetic alterations such as the loss of tumour protein 53 (TP53). The loss of the retinoblastoma tumour suppressor encoded by the RB1 locus is a well-characterised occurrence in many tumour types; however, its role in breast cancer is less clear with many reports demonstrating a loss of heterozygosity that does not correlate with a loss of RB1 protein expression.


METHODS
We used gene expression analysis for tumour subtyping and polymorphic markers located at the RB1 locus to assess the frequency of loss of heterozygosity in 88 primary human breast carcinomas and their normal tissue genomic DNA samples.


RESULTS
RB1 loss of heterozygosity was observed at an overall frequency of 39%, with a high frequency in basal-like (72%) and luminal B (62%) tumours. These tumours also concurrently showed low expression of RB1 mRNA. p16INK4a was highly expressed in basal-like tumours, presumably due to a previously reported feedback loop caused by RB1 loss. An RB1 loss of heterozygosity signature was developed and shown to be highly prognostic, and was potentially a predictive marker of response to neoadjuvant chemotherapy.


CONCLUSIONS
These results suggest that the functional loss of RB1 is common in basal-like tumours, which may play a key role in dictating their aggressive biology and unique therapeutic responses.
Herschkowitz
Jason I
JI
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, 27599, USA.
He
Xiaping
X
Fan
Cheng
C
Perou
Charles M
CM
D001943:Breast Neoplasms / Q000145:classification / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002277:Carcinoma / Q000145:classification / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002455:Cell Division; D019938:Cyclin D1 / Q000096:biosynthesis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D016161:Genes, Retinoblastoma; D019940:Genes, bcl-1; D019942:Genes, p16; D006801:Humans; D019656:Loss of Heterozygosity; D020360:Neoadjuvant Therapy; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000502:physiology*
C530104:CCND1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016160:Retinoblastoma Protein; D019938:Cyclin D1
Hum Pathol. 2007 Feb;38(2):197-204
17234468
Nature. 2000 Aug 17;406(6797):747-52
10963602
Cell. 1995 May 5;81(3):323-30
7736585
BMC Genet. 2005 Nov 04;6:53
16269091
Oncogene. 2007 Sep 20;26(43):6307-18
17452985
N Engl J Med. 2004 Dec 30;351(27):2817-26
15591335
Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8561-6
15939874
Int J Cancer. 1998 Feb 20;79(1):71-5
9495362
Cancer Res. 2004 Jan 1;64(1):64-71
14729609
Clin Cancer Res. 2008 Apr 1;14(7):2199-209
18381962
Cancer Res. 2005 Oct 15;65(20):9155-8
16230372
Cancer Cell. 2004 May;5(5):489-500
15144956
Br J Cancer. 1998 Dec;78(12):1661-8
9862580
Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13550-5
16141321
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23
12829800
Mod Pathol. 2006 Feb;19(2):264-71
16341146
Oncogene. 1998 Jul 16;17(2):199-205
9674704
Clin Cancer Res. 2007 Apr 15;13(8):2329-34
17438091
Science. 1988 Jul 8;241(4862):218-21
3388033
Cytogenet Cell Genet. 1992;60(3-4):190-3
1354594
Mol Cancer. 2007 Jan 18;6:7
17233903
Nature. 1995 Jun 8;375(6531):503-6
7777060
Am J Pathol. 1996 Jul;149(1):15-20
8686738
Oncogene. 1989 Jun;4(6):725-9
2543943
J Clin Invest. 2007 Jan;117(1):218-28
17160137
Dis Markers. 2001;17(2):99-109
11673656
Mol Carcinog. 2000 Nov;29(3):151-8
11108660
Mol Med. 1998 Dec;4(12):807-22
9990866
Cancer Res. 1994 Dec 1;54(23):6078-82
7954450
J Clin Oncol. 2006 Apr 10;24(11):1656-64
16505416
Virchows Arch. 2002 Dec;441(6):577-83
12461615
Clin Cancer Res. 2005 Aug 15;11(16):5678-85
16115903
Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74
11553815
Cancer Res. 1994 Nov 15;54(22):5816-20
7954407
Mol Diagn Ther. 2007;11(1):63-70
17286451
Am J Hum Genet. 2003 Feb;72(2):253-69
12541220
Cancer Res. 1992 May 15;52(10):2991-4
1581913
Breast Cancer Res. 2006;8(2):R23
16626501
Cancer Cell. 2007 Nov;12(5):479-91
17996651
Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
11309499
Appl Immunohistochem Mol Morphol. 2006 Mar;14(1):63-70
16540733
Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2952-7
10077618
Nat Rev Cancer. 2006 Feb;6(2):99-106
16491069
Nat Genet. 2002 Jul;31(3):285-8
12068296
Cancer Cell. 2006 Dec;10(6):529-41
17157792
Cancer Res. 2005 May 15;65(10):4059-66
15899795
Breast Cancer Res Treat. 2001 May;67(1):61-70
11518467
N Engl J Med. 2002 Dec 19;347(25):1999-2009
12490681
J Clin Oncol. 2006 Sep 10;24(26):4236-44
16896004
Clin Cancer Res. 2000 Jul;6(7):2777-87
10914724
Genes Dev. 2007 Jan 1;21(1):49-54
17210787
Science. 1988 Oct 14;242(4876):263-6
3175651
Nature. 2007 Aug 16;448(7155):811-5
17700700
Genome Biol. 2007;8(5):R76
17493263
Hum Mol Genet. 2008 May 15;17(10):1363-72
18211953
Science. 1996 Dec 6;274(5293):1672-7
8939849
Clin Chim Acta. 2005 Aug;358(1-2):75-80
15921673
Hum Mutat. 2002 Nov;20(5):408
12402348
BMC Genomics. 2006 Apr 27;7:96
16643655
Oncogene. 1993 Aug;8(8):2127-33
8336939