Larson Pamela S, Schlechter Benjamin L, King Chia-Lin, Yang Qiong, Glass Chelsea N, Mack Charline, Pistey Robert, de Las Morenas Antonio, Rosenberg Carol L
Department of Pathology and Laboratory Medicine, Boston University Medical Center, Boston, MA, USA.
BMC Cancer. 2008 Mar 6;8:68. doi: 10.1186/1471-2407-8-68.
CDKN1C (also known as p57KIP2) is a cyclin-dependent kinase inhibitor previously implicated in several types of human cancer. Its family members (CDKN1A/p21CIP1 and B/p27KIP1) 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.
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.
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.
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.
CDKN1C（也称为p57KIP2）是一种细胞周期蛋白依赖性激酶抑制剂，先前已涉及多种类型的人类癌症。其家族成员（CDKN1A/p21CIP1和B/p27KIP1）与乳腺癌有关，但关于CDKN1C作用的信息有限。我们推测CDKN1C表达降低可能参与人类乳腺癌的体内发生过程。
我们利用内含子多态性，测定了82例乳腺癌中CDKN1C以及其周围11p15.5区域的等位基因失衡或杂合性缺失（AI/LOH）发生率。我们使用定量实时PCR（qPCR）检测了10例癌症中的CDKN1C mRNA水平，使用免疫组织化学（IHC）检测了20例癌症中的CDKN1C蛋白水平。所有样本均通过激光显微切割获得。数据采用标准统计检验进行分析。
11p15.5处的AI/LOH发生在28/73（38%）例信息充分的癌症中，但CDKN1C本身仅在3/16（19%）例癌症中发生AI/LOH（p = 无显著性差异）。相比之下，9/10（90%）例癌症中的CDKN1C mRNA水平降低（p < 0.0001），范围为配对正常上皮的2% - 60%。同样，CDKN1C蛋白染色在19/20（95%）例正常上皮中可见，但在仅7/14（50%）例原位癌（CIS）中可见（p < 0.004），在5/18（28%）例浸润癌（IC）中可见（p < 0.00003）。这种降低似乎主要是由于肌上皮层细胞中CDKN1C表达缺失，在17/20（85%）例正常小叶中该层细胞染色强烈，但在0/14（0%）例CIS中染色强烈（p < 0.00001）。相比之下，管腔细胞在各组织学类型中染色强度较低且呈局灶性，较为一致。CDKN1C降低与肿瘤分级、组织学类型、雌激素受体（ER）、孕激素受体（PR）或人表皮生长因子受体2（HER2）状态无明显关联。
CDKN1C在大多数乳腺癌病例的正常上皮中表达，主要在肌上皮层。在大多数乳腺癌中，其在mRNA和蛋白水平均降低，且似乎不是由该基因处的AI/LOH介导的。因此，CDKN1C可能是一种乳腺癌肿瘤抑制因子。
