Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
PLoS One. 2009 Dec 31;4(12):e8404. doi: 10.1371/journal.pone.0008404.
Approximately one out of every ten cases of epithelial ovarian cancer (EOC) is inherited. The majority of inherited cases of EOC result from mutations in the breast cancer associated gene 1 (BRCA1). In addition to mutation of BRCA1, mutation of the p53 gene is often found in patients with inherited breast and ovarian cancer syndrome.
METHODOLOGY/PRINCIPAL FINDINGS: We investigated the role of loss of function of BRCA1 and p53 in ovarian cancer development using mouse models with conditionally expressed alleles of Brca1 and/or p53. Our results show that ovary-specific Cre-recombinase-mediated conditional inactivation of both Brca1(LoxP/LoxP) and p53(LoxP/LoxP) resulted in ovarian or reproductive tract tumor formation in 54% of mice, whereas conditional inactivation of either allele alone infrequently resulted in tumors (< or =5% of mice). In mice with conditionally inactivated Brca1(LoxP/LoxP) and p53(LoxP/LoxP), ovarian tumors arose after long latency with the majority exhibiting histological features consistent with high grade leiomyosarcomas lacking expression of epithelial, follicular or lymphocyte markers. In addition, tumors with conditional inactivation of both Brca1(LoxP/LoxP) and p53(LoxP/LoxP) exhibited greater genomic instability compared to an ovarian tumor with inactivation of only p53(LoxP/LoxP).
CONCLUSIONS/SIGNIFICANCE: Although conditional inactivation of both Brca1 and p53 results in ovarian tumorigenesis, our results suggest that additional genetic alterations or alternative methods for targeting epithelial cells of the ovary or fallopian tube for conditional inactivation of Brca1 and p53 are required for the development of a mouse model of Brca1-associated inherited EOC.
上皮性卵巢癌（EOC）每 10 例中约有 1 例为遗传性。大多数 EOC 的遗传性病例是由乳腺癌相关基因 1（BRCA1）的突变引起的。除了 BRCA1 的突变外，遗传性乳腺癌和卵巢癌综合征患者中经常发现 p53 基因的突变。
方法/主要发现：我们使用条件性表达 Brca1 和/或 p53 等位基因的小鼠模型，研究了 BRCA1 和 p53 功能丧失在卵巢癌发展中的作用。我们的结果表明，卵巢特异性 Cre 重组酶介导的 Brca1（LoxP/LoxP）和 p53（LoxP/LoxP）的条件性失活，导致 54%的小鼠中出现卵巢或生殖道肿瘤形成，而单独失活任一等位基因很少导致肿瘤（<或=5%的小鼠）。在条件性失活 Brca1（LoxP/LoxP）和 p53（LoxP/LoxP）的小鼠中，卵巢肿瘤在潜伏期后出现，大多数肿瘤具有高级别平滑肌肉瘤的组织学特征，缺乏上皮、滤泡或淋巴细胞标志物的表达。此外，与仅 p53（LoxP/LoxP）失活的卵巢肿瘤相比，同时失活 Brca1（LoxP/LoxP）和 p53（LoxP/LoxP）的肿瘤表现出更大的基因组不稳定性。
结论/意义：尽管同时失活 Brca1 和 p53 导致卵巢肿瘤发生，但我们的结果表明，需要额外的遗传改变或替代方法来靶向卵巢或输卵管的上皮细胞，以实现 Brca1 相关遗传性 EOC 的小鼠模型的发展。
