Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells
Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells
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DOI：
10.1158/0008-5472.can-05-2612
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发表时间：
2005-12-01
期刊：
影响因子：
11.2
通讯作者：
Brugge, JS
中科院分区：
文献类型：
--
作者：
Isakoff, SJ;Engelman, JA;Brugge, JS
磷酸肌醇3-激酶（PI3K）途径的激活与多种癌症的发病机理有关。最近，编码p110α的基因中的突变。 PI3K（PIK3CA）的催化亚基已在几种人类癌症中鉴定出来。该突变主要导致单个氨基酸取代，在外显子9或20中，突变> 85％。多次研究表明，在18％至40％的乳腺癌中观察到这些突变。但是，这些PIK3CA突变的表型作用尚未在乳腺上皮细胞中进行检查。本文中，我们研究了MCF-10A永生化的乳腺上皮细胞系中两个最常见的变体E545K和H1047R的活性。这两种变体的PI3K活性都比野生型P110 alpha更高，但对药理PI3K抑制仍然敏感。此外，乳腺上皮细胞中p110α突变体的表达诱导乳腺肿瘤细胞的多种表型改变，包括软琼脂中锚固非依赖性的增殖，生长因子非依赖性的增殖和抗厌氧菌的保护。这些突变体p110α同工型的表达也赋予对紫杉醇的耐药性，并在三维基底膜培养物中诱导异常的乳腺腺泡形态发生。总之，这些数据支持以下观点：PIK3CA中与癌症相关的突变可能显着有助于乳腺癌的发病机理，并代表了治疗性抑制的有吸引力的靶标。
Activation of the phosphoinositide 3-kinase (PI3K) pathway has been implicated in the pathogenesis of a variety of cancers. Recently, mutations in the gene encoding the p110 alpha. catalytic subunit of PI3K (PIK3CA) have been identified in several human cancers. The mutations primarily result in single amino acid substitutions, with >85% of the mutations in either exon 9 or 20. Multiple studies have shown that these mutations are observed in 18% to 40% of breast cancers. However, the phenotypic effects of these PIK3CA mutations have not been examined in breast epithelial cells. Herein, we examine the activity of the two most common variants, E545K and H1047R, in the MCF-10A immortalized breast epithelial cell line. Both variants display higher PI3K activity than wild-type p110 alpha yet remain sensitive to pharmacologic PI3K inhibition. In addition, expression of p110 alpha mutants in mammary epithelial cells induces multiple phenotypic alterations characteristic of breast tumor cells, including anchorage-independent proliferation in soft agar, growth factor-independent proliferation, and protection from anoikis. Expression of these mutant p110 alpha isoforms also confers increased resistance to paclitaxel and induces abnormal mammary acinar morphogenesis in three-dimensional basement membrane cultures. Together, these data support the notion that the cancer-associated mutations in PIK3CA may significantly contribute to breast cancer pathogenesis and represent attractive targets for therapeutic inhibition.