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

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 triple‐negative 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; 00: 000–000)

[1]  S. Kimura,et al.  CD151 dynamics in carcinoma–stroma interaction: integrin expression, adhesion strength and proteolytic activity , 2007, Laboratory Investigation.

[2]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.

[3]  D. Carter TNM Classification of Malignant Tumors , 1998 .

[4]  R. Gray,et al.  Tumor necrosis is a prognostic predictor for early recurrence and death in lymph node-positive breast cancer: a 10-year follow-up study of 728 Eastern Cooperative Oncology Group patients. , 1993, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  T. Hasebe,et al.  Significance of Basic Fibroblast Growth Factor and Fibroblast Growth Factor Receptor Protein Expression in the Formation of Fibrotic Focus in Invasive Ductal Carcinoma of the Breast , 1997, Japanese journal of cancer research : Gann.

[6]  A. Ochiai,et al.  Proliferative activity of intratumoral fibroblasts is closely correlated with lymph node and distant organ metastases of invasive ductal carcinoma of the breast. , 2000, The American journal of pathology.

[7]  D. Allred,et al.  Prognostic and predictive factors in breast cancer by immunohistochemical analysis. , 1998, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[8]  E. van Marck,et al.  Intratumoral hypoxia resulting in the presence of a fibrotic focus is an independent predictor of early distant relapse in lymph node‐negative breast cancer patients , 2001, Histopathology.

[9]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[10]  Brian Bierie,et al.  Under Pressure: Stromal Fibroblasts Change Their Ways , 2005, Cell.

[11]  T. Rosol,et al.  Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner. , 2008, Cancer research.

[12]  Rameen Beroukhim,et al.  Molecular characterization of the tumor microenvironment in breast cancer. , 2004, Cancer cell.

[13]  E. Kubista,et al.  Differential gene expression profile in breast cancer-derived stromal fibroblasts , 2007, Breast Cancer Research and Treatment.

[14]  G. Bratthauer,et al.  Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. , 2000, Cancer research.

[15]  T. Hasebe,et al.  A Proposal for a New Histological Classification Scheme for Predicting Short‐term Tumor Recurrence and Death in Patients with Invasive Ductal Carcinoma of the Breast , 1998, Japanese journal of cancer research : Gann.

[16]  S. Hirohashi,et al.  Fibrotic focus in infiltrating ductal carcinoma of the breast: A significant histopathological prognostic parameter for predicting the long-term survival of the patients , 1998, Breast Cancer Research and Treatment.

[17]  Satoshi Matsumoto,et al.  Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas , 2002, Nature Genetics.

[18]  H. Kiaris,et al.  Evidence for nonautonomous effect of p53 tumor suppressor in carcinogenesis. , 2005, Cancer research.

[19]  C K Osborne,et al.  Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  A. Ochiai,et al.  Prognostic Significance of Fibrotic Focus in Invasive Ductal Carcinoma of the Breast: A Prospective Observational Study , 2002, Modern Pathology.

[21]  I. Haviv,et al.  Breast-Cancer Stromal Cells with TP 53 Mutations , 2008 .

[22]  A. Ochiai,et al.  Highly Proliferative Fibroblasts Forming Fibrotic Focus Govern Metastasis of Invasive Ductal Carcinoma of the Breast , 2001, Modern Pathology.

[23]  I. Haviv,et al.  Breast-cancer stromal cells with TP53 mutations. , 2008, The New England journal of medicine.

[24]  Jiri Bartek,et al.  Cell-cycle checkpoints and cancer , 2004, Nature.

[25]  F. Pépin,et al.  Stromal gene expression predicts clinical outcome in breast cancer , 2008, Nature Medicine.

[26]  P. Platzer,et al.  Breast-cancer stromal cells with TP53 mutations and nodal metastases. , 2007, The New England journal of medicine.

[27]  Robert D. Cardiff,et al.  Selective Evolution of Stromal Mesenchyme with p53 Loss in Response to Epithelial Tumorigenesis , 2005, Cell.

[28]  M. Campone,et al.  Prognostic impact of syndecan-1 expression in invasive ductal breast carcinomas , 2008, British Journal of Cancer.

[29]  W. McGuire,et al.  Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer. , 1993, Journal of the National Cancer Institute.

[30]  M. Hollstein,et al.  p53 and human cancer: the first ten thousand mutations. , 2000, Advances in cancer research.

[31]  H. Bloom,et al.  Histological Grading and Prognosis in Breast Cancer , 1957, British Journal of Cancer.

[32]  Edith A Perez,et al.  Estrogen- and progesterone-receptor status in ECOG 2197: comparison of immunohistochemistry by local and central laboratories and quantitative reverse transcription polymerase chain reaction by central laboratory. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  Anthony Rhodes,et al.  American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. , 2007, Archives of pathology & laboratory medicine.

[34]  D. Newgreen,et al.  Induction of epithelial to mesenchymal transition in PMC42-LA human breast carcinoma cells by carcinoma-associated fibroblast secreted factors , 2007, Breast Cancer Research.

[35]  G. Ishii,et al.  Histopathologic factors significantly associated with initial organ-specific metastasis by invasive ductal carcinoma of the breast: a prospective study. , 2008, Human pathology.

[36]  P. V. van Diest,et al.  Multivariate prognostic evaluation of the mitotic activity index and fibrotic focus in node-negative invasive breast cancers. , 2005, European journal of cancer.

[37]  Gabriel S. Eichler,et al.  Signal pathway profiling of epithelial and stromal compartments of colonic carcinoma reveals epithelial-mesenchymal transition , 2008, Oncogene.

[38]  D. Allred,et al.  Progesterone receptor by immunohistochemistry and clinical outcome in breast cancer: a validation study , 2004, Modern Pathology.