Sierra A, Castellsagué X, Tórtola S, Escobedo A, Lloveras B, Peinado M A, Moreno A, Fabra A
Departament Cancer i Metàstasis, Institut de Recerca Oncològica, d'Anatomia Patològica, Barcelona, Spain.
Clin Cancer Res. 1996 Nov;2(11):1887-94.
The Bcl-2 proto-oncogene extends cell survival but does not confer any proliferative advantage to cells that express it. Thus, the loss of apoptosis may have a role in progression allowing the acquisition of additional mutations. To determine whether apoptosis loss at diagnosis is associated with the metastatic advantage of ductal breast carcinomas and to examine the relationship between Bcl-2 expression, p53, and tumor cell death status, we examined tumor samples from 116 patients diagnosed with T1 (2 cm or less) breast cancer with (n = 49) or without (n = 67) lymph node metastases. Apoptosis loss in histological sections was considered when <1% of tumor nuclei were stained with terminal deoxynucleotidyl transferase labeled with biotin. We studied the expression of Bcl-2 and p53 by immunohistochemistry and in 37 p53 mutations by single-strand conformational polymorphism analysis and cycle sequencing. Multivariate logistic regression modeling was used to estimate prevalence odds ratios (pORs) for apoptosis loss and presence of lymph node metastases. Patients with marked apoptosis loss in their tumor cells were about 5 times more likely to present lymph node metastases than those with no apoptosis loss in their tumor cells (adjusted pOR, 4.7; 95% confidence interval, 1.4-15.6; trend test, P = 0.008). Bcl-2 expression was strongly associated with both apoptosis loss (pOR, 6.9; trend test, P < 0.0001) and presence of lymph node metastases (pOR, 5.7; trend test, P = 0.002). These associations were more evident in histological grade I and II tumors than in poorly differentiated histological grade III tumors and in p53-negative tumors than in p53-positive tumors. This study demonstrates for the first time that the lymphatic progression of T1 human breast cancer is strongly related to apoptosis loss.
Bcl-2原癌基因可延长细胞存活时间，但不会赋予表达它的细胞任何增殖优势。因此，凋亡缺失可能在肿瘤进展中起作用，使细胞能够获得更多突变。为了确定诊断时凋亡缺失是否与导管乳腺癌的转移优势相关，并研究Bcl-2表达、p53与肿瘤细胞死亡状态之间的关系，我们检测了116例诊断为T1期（2厘米或更小）乳腺癌且有（n = 49）或无（n = 67）淋巴结转移患者的肿瘤样本。当组织学切片中<1%的肿瘤细胞核被生物素标记的末端脱氧核苷酸转移酶染色时，认为存在凋亡缺失。我们通过免疫组织化学研究了Bcl-2和p53的表达，并通过单链构象多态性分析和循环测序研究了37个p53突变。采用多变量逻辑回归模型估计凋亡缺失和淋巴结转移存在的患病率比值比（pOR）。肿瘤细胞凋亡明显缺失的患者出现淋巴结转移的可能性比肿瘤细胞无凋亡缺失的患者高约5倍（校正pOR，4.7；95%置信区间，1.4 - 15.6；趋势检验，P = 0.008）。Bcl-2表达与凋亡缺失（pOR，6.9；趋势检验，P < 0.0001）和淋巴结转移存在（pOR，5.7；趋势检验，P = 0.002）均密切相关。这些关联在组织学I级和II级肿瘤中比在低分化的组织学III级肿瘤中更明显，在p53阴性肿瘤中比在p53阳性肿瘤中更明显。本研究首次表明，T1期人类乳腺癌的淋巴转移与凋亡缺失密切相关。
