E2F3b over-expression in ovarian carcinomas and in BRCA1 haploinsufficient fallopian tube epithelium.
E2F3b over-expression in ovarian carcinomas and in BRCA1 haploinsufficient fallopian tube epithelium.
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E2F3b 在卵巢癌和 BRCA1 单倍体不足的输卵管上皮中过度表达。
DOI：
10.1002/gcc.21990
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Swisher,ElizabethM
中科院分区：
文献类型：
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作者：
Smith,NaLu;Welcsh,Piri;Press,JoshuaZ;Agnew,KathyJ;Garcia,Rochelle;Swisher,ElizabethM
我们先前已经证明，E2F3癌基因在BRCA 1突变的女性输卵管上皮（FTE）中作为“癌前表达谱”的一部分上调。我们研究了BRCA 1或BRCA 2突变或两种基因均为野生型的女性FTE和癌中E2F3的表达。与邻近的正常FTE相比，BRCA 1突变女性组织学正常的FTE中TP53阳性细胞灶显著更多，而野生型或BRCA 2突变个体中则没有，E2F3蛋白过度表达发生在局灶性增殖增加的背景下，这可能解释了BRCA 1突变女性输卵管TP53病灶的肿瘤发生潜力增加。为了评估E2F3失调在卵巢或输卵管癌发生中的机制，我们研究了野生型卵巢癌和与生殖系BRCA 1和BRCA 2突变相关的卵巢癌中的E2F3及其两种亚型E2F3a和E2F3b。E2F3b的表达与BRCA 1的表达相关，而E2F3a的表达与BRCA 1的表达无关。在来自BRCA1突变或BRCA1和BRCA2野生型女性的FTE原代培养物中，siRNA诱导的BRCA1缺陷导致E2F3b表达增加，但不导致E2F3a表达增加。我们的研究结果表明，E2F3和BRCA 1在功能上是相互联系的，正常FTE中BRCA 1单倍不足可能导致上皮内瘤变发生前E2F3带的上调增加增殖。这些数据支持E2F3bup调控是BRCA1突变携带者FTE中重要的癌前事件。© 2012 Wiley Periodicals，Inc.
We have previously shown that theE2F3oncogene is up‐regulated as part of a “preneoplastic expression profile” in fallopian tube epithelium (FTE) of women withBRCA1mutations. We studiedE2F3expression in FTE and carcinomas of women withBRCA1orBRCA2mutations or wildtype for both genes. Significantly more foci of TP53 positive cells in histologically normal FTE from women withBRCA1mutations but not in wildtype orBRCA2mutated individuals had E2F3 protein overexpression relative to adjacent normal FTE, which occurred in the context of focally increased proliferation, potentially explaining the increased neoplastic potential of tubal TP53 foci in women withBRCA1mutations. To assess mechanisms ofE2F3deregulation in ovarian or tubal carcinogenesis, we studiedE2F3and its two isoforms E2F3a and E2F3b in wild‐type ovarian carcinomas and ovarian carcinomas associated with germlineBRCA1andBRCA2mutations. The expression ofE2F3b, but notE2F3a, was correlated with the expression ofBRCA1in all three genetic groups. In primary cultures of FTE from women withBRCA1mutation or wildtype forBRCA1andBRCA2, siRNA‐inducedBRCA1deficiency led to increasedE2F3bbut notE2F3aexpression. Our results suggest thatE2F3bandBRCA1are functionally connected, andBRCA1haploinsufficiency in normal FTE may lead to up‐regulation ofE2F3band increased proliferation before the development of intraepithelial neoplasia. These data support thatE2F3bup‐regulation is an important preneoplastic event in FTE fromBRCA1mutation carriers. © 2012 Wiley Periodicals, Inc.