Roy D, Calaf G, Hei T K
Center for Radiological Research, Vanderbilt Clinic 11-218, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Carcinogenesis. 2001 Oct;22(10):1685-92. doi: 10.1093/carcin/22.10.1685.
The development of human breast cancer is a complex multi-step process that depends on various exogenous and endogenous factors that modulate the transformation of normal human breast epithelial cells into neoplastic ones. Using a spontaneously-immortalized human breast epithelial (MCF-10F) cell line, we have shown previously that radiation, in combination with estrogen, induces a stepwise neoplastic transformation of this cell line. In the present study, we investigate the incidence of microsatellite instability and loss of heterozygosity using a battery of markers on chromosomes 6 and 17, we correlate the genetic alteration with the malignant transformation of the MCF-10F cell line ranging from altered morphology to increase in proliferative rate, anchorage independent growth and tumorigenicity in nude mice. Microsatellite markers were selected from the hot spot regions (6q21-q27, 17p12-p13.3 and 17q12-q21) of both chromosomes. We found that the frequency of allelic imbalance occurs at the different stages of tumor progression with a range of 21 to 50% depending on the marker studied. The relatively high rate of allele imbalance at all these loci suggests the presence and inactivation of one or more tumor suppressor genes in these regions. Thus, the present data will be useful for systematic studies to identify the cellular and molecular changes associated with radiation-induced breast carcinogenesis.
人类乳腺癌的发展是一个复杂的多步骤过程，它取决于各种外源性和内源性因素，这些因素调节正常人类乳腺上皮细胞向肿瘤细胞的转化。我们之前使用自发永生化的人类乳腺上皮（MCF-10F）细胞系表明，辐射与雌激素联合使用可诱导该细胞系发生逐步的肿瘤转化。在本研究中，我们使用一系列位于6号和17号染色体上的标记物来研究微卫星不稳定性和杂合性缺失的发生率，我们将基因改变与MCF-10F细胞系的恶性转化相关联，这种转化范围从形态改变到增殖率增加、锚定非依赖性生长以及在裸鼠中的致瘤性。微卫星标记物是从两条染色体的热点区域（6q21-q27、17p12-p13.3和17q12-q21）中选择的。我们发现，等位基因不平衡的频率在肿瘤进展的不同阶段出现，根据所研究的标记物不同，范围在21%至50%之间。所有这些位点相对较高的等位基因不平衡率表明这些区域存在一个或多个肿瘤抑制基因并发生了失活。因此，本数据将有助于进行系统研究，以确定与辐射诱导的乳腺癌发生相关的细胞和分子变化。
