Bovine leukemia virus in human breast tissues

Abstract

Background: Disruption of the balance between apoptosis and proliferation is considered to be an important factor in the development and progression of tumor. In this study we determined the in vivo cell kinetics along the spectrum of apparently normal epithelium, hyper-plasia, preinvasive lesions and invasive carcinoma, in breast tissues affected by fibrocystic changes in which preinvasive and/or invasive lesions developed, as a model of breast carcinogenesis. Materials and method: A total of 32 areas of apparently normal epithelium and 135 ductal proliferative and neoplastic lesions were studied. More than one epithelial lesion per case was analyzed. The apoptotic index (AI) and the proliferative index (PI) were expressed as the percentage of TUNEL (TdT-mediated dUTP-nick end-labelling) and Ki-67 positive cells, respectively. The prolifera-tive/apoptotic index (P/A) was calculated for each case. Results: Statistical analysis demonstrated significant differences among the tissue groups for both indices (P < 0.0001). The Als and PIs were significantly higher in hyperplasia than in apparently normal epithelium (P = 0.04 and P = 0.0005, respectively), in atypi-cal hyperplasia than in hyperplasia (P = 0.01 and P = 0.04, respectively) and in invasive carcinoma than in in situ carcinoma (P = 0.0001 and P < 0.0001, respectively). The two indices were similar in atypical hyperplasia and in in situ carcinoma. The P/A index increased significantly from normal epithelium to hyperplasia (P = 0.01) and from preinvasive lesions to invasive carcinoma (P = 0.04), whereas it was decreased (NS) from hyperplasia to preinvasive lesions. A strong positive correlation between the Als and the Pls was found (r = 0.83; P < 0.0001). Conclusion: These findings suggest accelerating cell turnover along the continuum of breast carcinogenesis. Atypical hyper-plasias and in situ carcinomas might be kinetically similar lesions. In the transition from normal epithelium to hyperplasia and from preinvasive lesions to invasive carcinoma, the net growth of epithe-lial cells results from a growth imbalance in favour of proliferation. In the transition from hyperplasia to preinvasive lesions there is an imbalance in favour of apoptosis. Background: Clinical and experimental data have raised the possibility that surgical removal of the primary tumor promotes the growth of metastatic lesions. Purpose: This study was undertaken to determine the effect of wound healing drainages and postsurgical sera obtained from breast carcinoma (BC) patients on proliferation of dormant BC cells and to assess the role of HER2 oncoprotein in this proliferation. Method: Proliferation of dormant BC cells was evaluated in vitro by SRB colorimetric assay. Growth factors were identified by inhibition with specific antibodies and displacement of 125 I-EGF from its receptor. Cellular damage was measured by creatine phospho-kinase level. The role of HER2 was analyzed by removal of HER2 from the membrane and inhibition by the anti-HER2 monoclonal antibody herceptin. Results: Healing wound drainages and postsurgical sera from BC patients stimulated the in vitro growth of BC cells. Removal of the HER2 oncoprotein from BC cell membrane led to a dramatic decrease in the induced proliferation. Drainage-induced proliferation was around 50% inhibited by antibodies directed against EGF-like factors, including HB-EGF and TGF-α. Levels of these growth factors in postsurgical sera, as well as the level of drainage-induced proliferation, were directly correlated with the entity of surgery (r = 0.8, P = 0.0007 and r = 0.64, P = 0.009, respectively). Treatment of the tumor cells with herceptin, abolished the patients' drainage-induced proliferation when added to cultures before the growth stimulus. Conclusion: HER2 overexpression by BC cells plays a major role in the postsurgery rescue of metastatic BC cells from dormancy. Herceptin appears to inhibit this growth induction. A prospective randomized clinical trial of perioperative treatment with herceptin of BC patients is starting.