growth of malignant cells in vitro and in vivo. 6,10 These obserp21 WAF1/CIP1 is a universal cyclin-dependent kinase vations suggest that p21 functions as a tumor suppressor (cdk) inhibitor, the expression of which is regulated by protein. p53-dependent and p53-independent pathways. We ex-No mutations of p21 WAF1/CIP1 were detected in 315 samples amined p21 WAF1/CIP1 expression in and p53 status of 21 from 14 different types of human malignancy, 11 suggesting primary hepatocellular carcinomas (HCCs) by reversethat p21 WAF1/CIP1 , if involved in tumorigenesis, exerts its eftranscriptase polymerase chain reaction (RT-PCR) and fect(s) mainly on expression levels rather than on gene mutaby PCR single-strand conformation polymorphism tions. The p21 WAF1/CIP1 gene has a p53 transcriptional regula-(PCR-SSCP) analysis. p21 WAF1/CIP1 messenger RNA extory motif, 6 and the cells lacking functional p53 express very pression was reduced markedly in 8 of 21 HCCs (38.1%) low levels of p21 WAF1/CIP1 , 5,6,12 indicating that p53 regulates and 5 of these 8 HCCs bore p53 mutations. The relative p21 WAF1/CIP1 expression directly. However, recent studies indip21 WAF1/CIP1 messenger RNA expression value of HCCs cated that p53-independent pathways may also lead to inwith p53 mutations (.73 { .13 U, n Å 6) was significantly creased p21 WAF1/CIP1 expression. 13-17 lower than that of HCCs with wild-type p53 (1.00 { 0.21In a previous study, we found that the inactivation of p53 U, n Å 14; P õ .01). The p21 WAF1/CIP1 expression levels in and Rb tumor suppressor genes, 18-21 as well as allelic loss cancerous tissues (.73 { .13 U) were significantly reon chromosomes 4q, 8p, 13q, 16q, and 17p, [21][22][23][24][25][26][27] contribute to duced in comparison with those in noncancerous tissues multistage hepatocarcinogenesis. Recently, we demonstrated (.97 { .13 U) (P õ .01) in the 6 cases with p53 mutations.that p16 INK4 , a member of the cdk inhibitor family, is also These data indicate that p21 WAF1/CIP1 expression in HCCs involved in hepatocarcinogenesis. 27 To determine whether is predominantly regulated by dependence on p53 and p21 WAF1/CIP1 participates in hepatocarcinogenesis and there is that reduced p21 WAF1/CIP1 expression may participate in a relationship between its expression and the p53 status, we hepatocarcinogenesis. (HEPATOLOGY 1997;25:575-579.)analyzed p21 WAF1/CIP1 messenger RNA expression in and the p53 status of primary hepatocellular carcinomas (HCCs). The sequential formation, activation, and subsequent inactivation of a series of cyclin-cyclin dependent kinase (cdk) PATIENTS AND METHODScomplexes regulate the checkpoints that control cell cycle proSamples. Twenty-one HCCs and corresponding noncancerous liver gression. 1,2 In addition to positive regulation of cell cycle pro-tissues were obtained from specimens surgically resected at the Nagression by the activation of cyclin-cdk complexes, negative tional Cancer Center Hospital (Tokyo, Japan). The samples were regulation is achieved through cdk inhibitory proteins, which ...

A subset of EMPD, both intraepithelial and invasive, showed HER2 overexpression and gene amplification. These HER2 alterations were correlated with biologically aggressive EMPDs, i.e. those with deep invasion and lymph-node metastasis. Clinical trials of HER2-targeted therapy are awaited for improvement of the prognosis of patients with aggressive EMPD.

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The purpose of this study was to determine whether p53 protein expression in tumor stromal fibroblasts assessed immunohistochemically by the Allred score system is significantly associated with nodal metastasis by invasive ductal carcinoma (IDC), and significantly associated with the outcome of 1042 IDC patients according to adjuvant therapy status, UICC pTNM stage, and triplenegative IDC status, in multivariate analyses with well-known clinicopathological factors. The Allred scores for p53 expression in tumor stromal fibroblasts were significantly associated with the number of nodal metastases, and Allred scores of 4-8 for p53 in tumor stromal fibroblasts significantly increased the hazard rate for distant organ metastasis or for tumor death in the triple-negative IDC patients, and the UICC pTNM stage I, II, and III patients. The results indicated that p53 protein expression in tumor stromal fibroblasts is closely associated with the number of nodal metastases and the outcome of IDC patients. (Cancer Sci 2009; 100: 2101-2108 I t has recently been reported that the gene expression and protein expression profiles of the tumor stroma play very important roles in tumor progression in carcinoma, (1)(2)(3) and the interaction between tumor and stromal cells also plays a very important role in tumor progression by carcinoma.(4-6) We and others have already reported that a characteristic histological feature of tumor stroma, a fibrotic focus, is a very useful prognostic histological tumor stromal indicator for accurately predicting the outcome of patients with invasive ductal carcinoma (IDC), (7)(8)(9)(10) and that growth factors produced by tumor cells and tumor stromal cells play a very important role in tumor progression by IDC.(11) In addition, proliferative activity of tumor stromal fibroblasts plays a very important role in nodal metastasis and distant organ metastasis by IDC.(12,13) These findings strongly suggest a significant role of the tumor stroma in tumor progression by IDC.p53 is the most commonly mutated gene in human neoplasms, (14) and the p53 tumor suppressor protein is involved in the cell cycle, checkpoint control, repair of DNA damage, and apoptosis.(15,16) Also, besides their well-studied cell-autonomous role in cancer cells, mutations of the p53 tumor suppressor gene have been described in stromal fibroblasts of breast and prostate carcinoma in humans and experimental animals. (17)(18)(19)(20) A high frequency of p53 mutations in tumor cells and the surrounding stroma has also reported, (17) and p53 mutations in breast cancer stromal cells have been reported to be closely associated with nodal metastasis.(21) Based on the above findings, the p53 status of tumor stromal fibroblasts may play a very important role in carcinoma progression by IDC.The purpose of the present study was to determine whether p53 protein expression in tumor stromal fibroblasts is significantly associated with nodal metastasis by IDC, and significantly associated with the outcome of IDC patients with and without adjuvant th...

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