CDKN1C/p57kip2 is a candidate tumor suppressor gene in human breast cancer

doi:10.1186/1471-2407-8-68

BMC Cancer

Volume 8

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Larson PS
Schlechter BL
King CL
Yang Q
Glass CN
Mack C
Pistey R
de las Morenas A
Rosenberg CL

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Larson PS
Schlechter BL
King CL
Yang Q
Glass CN
Mack C
Pistey R
de las Morenas A
Rosenberg CL
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Research article

CDKN1C/p57^kip2is a candidate tumor suppressor gene in human breast cancer

Pamela S Larson¹^* , Benjamin L Schlechter²^* , Chia-Lin King² , Qiong Yang³ , Chelsea N Glass⁴ , Charline Mack¹ , Robert Pistey¹ , Antonio de las Morenas¹ and Carol L Rosenberg¹^,2

¹Department of Pathology and Laboratory Medicine, Boston University Medical Center, Boston MA USA

²Department of Medicine, Boston University Medical Center, Boston MA, USA

³Department of Biostatistics, Boston University School of Public Health, Boston MA, USA

⁴Division of Graduate Medical Sciences, Boston University Medical Sciences, Boston MA, USA

author email corresponding author email* Contributed equally

BMC Cancer 2008, 8:68doi:10.1186/1471-2407-8-68


Published:	6 March 2008

Abstract

Background

CDKN1C (also known as p57^KIP2) is a cyclin-dependent kinase inhibitor previously implicated in several types of human cancer. Its family members (CDKN1A/p21^CIP1and B/p27^KIP1) have been implicated in breast cancer, but information about CDKN1C's role is limited. We hypothesized that decreased CDKN1C may be involved in human breast carcinogenesis in vivo.

Methods

We determined rates of allele imbalance or loss of heterozygosity (AI/LOH) in CDKN1C, using an intronic polymorphism, and in the surrounding 11p15.5 region in 82 breast cancers. We examined the CDKN1C mRNA level in 10 cancers using quantitative real-time PCR (qPCR), and the CDKN1C protein level in 20 cancers using immunohistochemistry (IHC). All samples were obtained using laser microdissection. Data were analyzed using standard statistical tests.

Results

AI/LOH at 11p15.5 occurred in 28/73 (38%) informative cancers, but CDKN1C itself underwent AI/LOH in only 3/16 (19%) cancers (p = ns). In contrast, CDKN1C mRNA levels were reduced in 9/10 (90%) cancers (p < 0.0001), ranging from 2–60% of paired normal epithelium. Similarly, CDKN1C protein staining was seen in 19/20 (95%) cases' normal epithelium but in only 7/14 (50%) cases' CIS (p < 0.004) and 5/18 (28%) cases' IC (p < 0.00003). The reduction appears primarily due to loss of CDKN1C expression from myoepithelial layer cells, which stained intensely in 17/20 (85%) normal lobules, but in 0/14 (0%) CIS (p < 0.00001). In contrast, luminal cells displayed less intense, focal staining fairly consistently across histologies. Decreased CDKN1C was not clearly associated with tumor grade, histology, ER, PR or HER2 status.

Conclusion

CDKN1C is expressed in normal epithelium of most breast cancer cases, mainly in the myothepithelial layer. This expression decreases, at both the mRNA and protein level, in the large majority of breast cancers, and does not appear to be mediated by AI/LOH at the gene. Thus, CDKN1C may be a breast cancer tumor suppressor.