p53 expression in tumor stromal fibroblasts is associated with the outcome of patients with invasive ductal carcinoma of the breast

Abstract

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...

p53 expression in tumor-stromal fibroblasts forming and not forming fibrotic foci in invasive ductal carcinoma of the breast

“…19 In this study, a fibrotic focus diameter was also a significant outcome predictor for IDC patients of UICC pTNM stage II and IDC patients of UICC pTNM stage III, and IDCs with fibrotic foci greater than 8 mm in diameter showed a significantly higher Allred score for p53 in tumor-stromal fibroblasts forming fibrotic foci than IDCs with fibrotic foci of 8 mm or less in diameter. Thus, one can conclude that p53-expressing tumor-stromal fibroblasts located in both the inner and outer regions of fibrotic foci heighten the malignant potential of IDCs, probably accounting for the prognostic value of the fibrotic focus diameter.…”

“…Slides of the tumor cells immunostained for estrogen receptor, progesterone receptor, and p53 were scored using the Allred scoring system, as described previously, [26][27][28] and the Allred scores for estrogen receptor, progesterone receptor, and p53 expression in the tumor cells were classified into the following three categories 19 : (1) Allred score for estrogen receptor in tumor cells (0 or 2, 3-6, and 7 or 8); (2) Allred score for progesterone receptor in tumor cells (0 or 2, 3-6, and 7 or 8); and (3) Allred scores for p53 in tumor cells (0 or 2 or 3, 4-6, and 7 or 8). We modified the Allred scoring system to assess the nuclear expression of p53 in the tumor-stromal fibroblasts forming and not forming fibrotic foci, 19,20 and the Allred scores for p53 expression in tumorstromal fibroblasts forming and not forming fibrotic foci were classified into the following categories: (1) Allred scores for p53 in tumor-stromal fibroblasts forming fibrotic foci (0, 2, 3, and 4-8); and (2) Allred scores for p53 in tumor-stromal fibroblasts not forming fibrotic foci (0 or 2, 3, and 4-8) (Figures 2 and 3).…”

“…We modified the Allred scoring system to assess the nuclear expression of p53 in the tumor-stromal fibroblasts forming and not forming fibrotic foci, 19,20 and the Allred scores for p53 expression in tumorstromal fibroblasts forming and not forming fibrotic foci were classified into the following categories: (1) Allred scores for p53 in tumor-stromal fibroblasts forming fibrotic foci (0, 2, 3, and 4-8); and (2) Allred scores for p53 in tumor-stromal fibroblasts not forming fibrotic foci (0 or 2, 3, and 4-8) (Figures 2 and 3). Of the 1039 IDCs, 373 IDCs had fibrotic foci; we could not assess the Allred scores for p53 in tumor-stromal fibroblasts forming a fibrotic focus in 97 of the 373 IDCs with fibrotic foci because the immunohistochemistry examinations for these specimens were performed using tumor tissue sections that did not contain a fibrotic focus at the time of routine examination.…”

“…19,22 The IDCs were diagnosed preoperatively using needle biopsy, aspiration cytology, a mammography, or ultrasonography. All the patients were Japanese women, ranging in age from 23 to 72 years (median, 55 years).…”

“…15 However, some studies have reported that p53 mutations are not observed in the tumor stroma of breast cancer, 16,17 and the possibility of technical problem, eg polymerase chain reaction artifacts for the p53 gene abnormality, has been suggested by Campbell et al 18 We recently showed that p53 expression in tumor-stromal fibroblasts not forming fibrotic foci was a very important outcome predictor for IDC patients who had or had not received neoadjuvant therapy. 19,20 On the basis of the above findings, the p53 status of tumor-stromal fibroblasts not forming fibrotic foci probably has a very important function in tumor progression in IDCs.…”