Increased Proliferative Background in Healthy Women with BRCA1/2 Haploinsufficiency Is Associated with High Risk for Breast Cancer
Increased Proliferative Background in Healthy Women with BRCA1/2 Haploinsufficiency Is Associated with High Risk for Breast Cancer
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DOI：
10.1158/1055-9965.epi-13-0193
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发表时间：
2013-11-01
影响因子：
3.8
通讯作者：
Peretz, Tamar
中科院分区：
文献类型：
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作者：
Nisman, Benjamin;Kadouri, Luna;Peretz, Tamar
先前的研究表明，BRCA单倍不足与EGF受体（EGFR）信号通路的激活和健康女性乳腺上皮细胞增殖活性增加有关。我们假设这些过程可能反映在血清可溶性EGFR（sEGFR）和胸苷激酶1（TK 1）活性的表达中，它们分别是增殖途径的初始和最终步骤的信号。我们发现，BRCA 1/2突变的健康携带者（n = 80）表现出明显高于年龄匹配的对照组（P = 0.0003），TK 1活性在BRCA 1和BRCA 2突变的女性中相似（P = 0.74）。BRCA 1突变组sEGFR浓度显著高于对照组和BRCA 2突变组（P分别为0.013和0.002）。在随访期间，80名BRCA 1/2突变携带者中有4人患上了乳腺癌。这些妇女表现出显着更高的TK 1活性和sEGFR浓度略高于其他76 BRCA 1/2携带者（P = 0.04和0.09，分别）。所有肿瘤均为卵巢激素受体阴性，但显示EGFR高表达。本研究受到短期随访（平均27个月;范围5-45）的限制，导致样本量较小。BRCA 1和BRCA 2突变的妇女，经历了降低风险的双侧输卵管卵巢切除术（BSO）显示，与那些没有手术（P = 0.007和0.038，分别）显著较低的sEGFR。更大规模的前瞻性研究是必要的，以调查TK 1和sEGFR测量是否可能是有用的，以确定健康的BRCA 1/2携带者发展为乳腺癌的高风险;此外，sEGFR测量可以作为评估风险的有效工具之前和之后BSO。(C)2013年AACR。
Previous studies indicated that BRCA haploinsufficiency was associated with activation of the EGF receptor (EGFR) signaling pathway and increased proliferative activity in mammary epithelial cells of healthy women. We hypothesized that these processes might be reflected in the expression of serologic soluble EGFR (sEGFR) and thymidine kinase 1 (TK1) activity, which signal the initial and final steps of the proliferative pathway, respectively. We found that healthy carriers of BRCA1/2 mutations (n = 80) showed a significantly higher TK1 activity than age-matched controls (P = 0.0003), and TK1 activity was similar in women with BRCA1 and BRCA2 mutations (P = 0.74). The sEGFR concentration was significantly higher in women with BRCA1 than in controls and BRCA2 mutation (P = 0.013 and 0.002, respectively). During follow-up, four of 80 BRCA1/2 mutation carriers developed breast cancer. These women showed a significantly higher TK1 activity and somewhat higher sEGFR concentrations than the other 76 BRCA1/2 carriers (P = 0.04 and 0.09, respectively). All tumors were negative for ovarian hormone receptors, but showed a high EGFR expression. This study was limited by the short-term follow-up (mean, 27 months; range, 5-45), which resulted in a small sample size. Women with BRCA1 and BRCA2 mutations that had undergone risk-reducing bilateral salpingo-oophorectomy (BSO) showed significantly lower sEGFR compared with those without surgery (P = 0.007 and 0.038, respectively). Larger, prospective studies are warranted to investigate whether TK1 and sEGFR measurements may be useful for identifying healthy BRCA1/2 carriers with high risk of developing breast cancer; moreover, sEGFR measurements may serve as effective tools for assessing risk before and after BSO. (C) 2013 AACR.