Prognostic significance of the metastasis-inducing protein S100A4 (p9Ka) in human breast cancer
Authors: A Platt-Higgins
J H Winstanley
P S Rudland
C Renshaw
L Robertson
C R West
R Barraclough
Journal: Cancer Research (2000)
Discipline: CLINICAL MEDICINE
Keywords: S100A4; breast cancer; metastasis; prognosis; survival
Affiliations: School of Biological Sciences, Cancer Tissue Bank Research Center, University of Liverpool, United Kingdom.

Abstract:  The calcium-binding protein S100A4 is capable of inducing metastasis in rodent models for breast cancer. We now show that rabbit antibodies to recombinant rat S100A4 recognize specifically human S100A4 using Western blotting techniques and use them to assess the prognostic significance of S100A4 in primary tumors from a group of 349 patients treated between 1976 and 1982 for stage I and stage II breast cancer. The antibody stains normal breast tissue heterogeneously, but stains positively 41% of the carcinomas, leaving the remaining 59% as negatively stained. In addition to the carcinoma cells, some host stromal cells and lymphocytes are also stained, but these have been discounted in subsequent analyses. There is an association of staining of carcinomas for S100A4 with some tumor variables considered to be associated with poor prognosis for patients: tumor present in axillary lymph nodes (borderline P = 0.058), staining for c-erbB-3 (P = 0.002), cathepsin D (P = 0.024), and c-erbB-2 (P = 0.048). The association of staining for S100A4 with patient survival has been evaluated using life tables and analyzed using generalized Wilcoxon statistics. Eighty percent of the S100A4-negative patients but only 11% of the S100A4-positive patients are alive after 19 years of follow-up, and this association is highly significant (P &lt; 0.0001); the former have a median survival of &gt;228 months and the latter 47 months. The other tumor variables that show significant association with survival time are nodal status (P &lt; 0.0001), tumor size (P = 0.0035), histological grade (P = 0.013), staining for c-erbB-2 (P = 0.0015), estrogen receptor (P = 0.028), and p53 (P = 0.032). Analysis of the association of patients with carcinomas staining for S100A4 and their survival in subgroups defined by these other tumor variables shows that in each subgroup, staining for S100A4 is associated with poorer survival. Patients whose tumors stain for S100A4 and possess involved lymph nodes (P &lt; 0.0001), which are fixed to the chest wall (P = 0.015) or which stain for c-erbB-2 (P = 0.050), show a significant reduction in survival times over those with only S100A4-staining tumors. Patients with involved lymph nodes, or staining for c-erbB-2 in the S100A4-negative group fail to show any significant reduction in survival times. Multivariate regression analysis for 137 patients shows that staining for S100A4 is most highly correlated with patient deaths (P &lt; 0.0001), but involved lymph nodes (P = 0.001), fixed tumors (P = 0.0002), and high histological grade (P = 0.022) are also significant independent prognostic variables. These results suggest that in this group of patients, the metastasis-inducing protein S100A4 is most tightly correlated with patient demise. 

Retracted: No

PubPeer comments:
 Figure 13A. * Some panels representing different treatment groups and timepoints appear to show overlapping areas as shown with colored rectangles. Note that the red ellipses and arrows are part of the original figure. * In the case of the overlap highlighted with the blue boxes, a red-stained area is missing in one of the overlaps, but present in the other, suggesting this is not a simple overlap. ![file] , 
 Figure 13B. * Some panels representing different timepoints appear to show overlapping areas as shown with rectangles in the same color. * In the case of the pink and cyan overlaps, the zoom-factor appears to be different, suggesting that the scale bars might not be correct. * Overlaps found with the aid of ImageTwin.io by Markus Zlabinger. ![file] , 
 Figure 13D. * Two panels representing different treatment groups appear to show overlapping areas as shown with yellow rectangles ![file] , 
 Retraction, June 11, 2021: https: link.springer.com article 10.1007%2Fs10856-021-06549-z  This article has been retracted at the request of the authors due to the multiple errors in Fig. 13. As some in vivo data are flawed, the conclusions of the article are no longer viable. The authors sincerely apologize to readers and the journal for any inconvenience caused. The authors are repeating their study and will submit a corrected manuscript for peer review. All authors agree to this retraction. ,