Sierra A, Castellsagué X, Escobedo A, Lloveras B, García-Ramirez M, Moreno A, Fabra A
Departament i Càncer Metàstasis, Institut de Recerca Oncològica, Hospital Duran i Reynals, Ciutat Sanitaria i Universitaria de Bellvitge, Barcelona, Spain.
Int J Cancer. 2000 Mar 20;89(2):142-7.
We have examined whether the extended life span of cells induced by Bcl-2 in T(1) ductal breast carcinomas might favor the acquisition and accumulation of genetic alterations that induce lymph node metastases. We analyzed the expression of c-Myc, c-erbB-2 and epidermal growth factor receptor by immuno-histochemistry in a group of 142 T(1) (<2 cm) ductal breast carcinomas embedded in paraffin, previously studied for p53 mutation and Bcl-2 over-expression. We also measured the apoptotic status and estimated the excess risk (pOR) for lymph node metastasis according to the number of accumulated oncogene alterations and Bcl-2 and p53 expression. The linear relationship between number of oncogene alterations and presence of lymph node metastasis was statistically significant in Bcl-2-positive tumors (trend test, p = 0.03), p53-mutated tumors (trend test, p = 0.08) and tumors with loss of apoptosis (trend test, p = 0.08). Very large associations (pOR > 12) between the number of oncogene alterations and lymph node metastasis were observed among Bcl-2-positive tumors that showed increased loss of apoptosis (trend test, p = 0.03). Furthermore, in p53-negative tumors, a strong linear association was found between the number of oncogene alterations and risk of lymph node metastasis among Bcl-2-positive tumors (trend test, p = 0.03). In human T(1) ductal breast carcinoma, over-expression of Bcl-2 along with loss of apoptosis might render breast cancer cells susceptible to the acquisition of additional genetic lesions related to disease progression among p53-negative tumors. Thus, in breast cancer, there are at least 2 pathways to progression: Bcl-2- and p53-dependent mechanisms.
我们研究了Bcl-2诱导的T(1)期乳腺导管癌细胞寿命延长是否可能有利于诱导淋巴结转移的基因改变的获得和积累。我们通过免疫组织化学分析了一组142例石蜡包埋的T(1)期（<2 cm）乳腺导管癌中c-Myc、c-erbB-2和表皮生长因子受体的表达，这些病例之前已研究过p53突变和Bcl-2过表达情况。我们还根据累积的癌基因改变数量以及Bcl-2和p53表达情况测量了凋亡状态并估计了淋巴结转移的超额风险（pOR）。在Bcl-2阳性肿瘤（趋势检验，p = 0.03）、p53突变肿瘤（趋势检验，p = 0.08）和凋亡缺失的肿瘤（趋势检验，p = 0.08）中，癌基因改变数量与淋巴结转移之间的线性关系具有统计学意义。在凋亡缺失增加的Bcl-2阳性肿瘤中，观察到癌基因改变数量与淋巴结转移之间存在非常大的关联（pOR > 12）（趋势检验，p = 0.03）。此外，在p53阴性肿瘤中，发现Bcl-2阳性肿瘤的癌基因改变数量与淋巴结转移风险之间存在强线性关联（趋势检验，p = 0.03）。在人类T(1)期乳腺导管癌中，Bcl-2过表达以及凋亡缺失可能使乳腺癌细胞在p53阴性肿瘤中易于获得与疾病进展相关的额外基因损伤。因此，在乳腺癌中，至少有2条进展途径：Bcl-2依赖和p53依赖机制。
