目的 研究乳腺癌及其不同亚型中表皮生长因子受体(epidermal growth factor receptor,EGFR)、磷脂酰肌醇3激酶(phosphoinositide 3 kinase,PI3K)及其磷酸化蛋白p-H3K的表达特点,并分析其与临床病理特征之间的相关性,探讨PI3K信号通路中PI3K及其磷酸化在乳腺癌发生发展过程中的作用.方法 选取2005年1月至2010年6月新疆医科大学附属肿瘤医院初诊的女性浸润性乳腺癌117例,按照免疫组化雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PR)和人表皮生长因子受体2 (human epidermalgrowth factor receptor-2,HER2)结果分子分型(HER2++者进一步行FISH检测明确状态),其中三阴型乳腺癌组(TN组)28例,HER2过表达型乳腺癌组(HER2+组)12例和管腔上皮型乳腺癌组(Luminal组)77例.应用免疫组化SP法检测乳腺癌及其癌旁组织中EGFR、PI3K和p-PI3K的表达情况,并分析其在乳腺癌及其不同亚型中的表达特点,以与临床病理特征之间的关系.结果 ①PI3K和p-PI3K在乳腺癌组织中的阳性表达率及程度均高于癌旁组织,差异有统计学意义(x2=27.589,P ＜0.001;x2=49.327,P＜0.001).同样,EGFR在乳腺癌与癌旁组织中的表达差异也有统计学意义(x2=10.920,P=0.004).②TN组和HER2+组中PI3K和p-PI3K的阳性表达率相似,但显著低于Lumin-al,而EGFR在TN组中阳性表达率明显高于其他2组,差异均具有统计学意义(x2=9.842,P=0.037;x2=13.423,P=0.006;x2=12.410,P=0.012).PI3K、EGFR仅在TN组与Luminal组间的表达差异有统计学意义(x2 =7.835,P=0.020;x2=11.791,P=0.003),p-PI3K在TN组与Luminal组间及HER2+组与Lu-minal组间的表达差异均有统计学意义(x2=9.336,P =0.009;x2 =7.361,P=0.025),其余组间比较无显著差异.③与PI3K相比,乳腺癌中p-PI3K的阳性表达率显著升高,2者呈显著正相关(r=0.324,P＜0.001).但不同亚型中PI3K和p-PI3K表达的相关性却存在不同,其中TN组和HER2+组中2者表达均无相关性(r =0.222,P=0.257;r=0.410,P=0.185),而在Luminal组中2者的表达呈显著正相关(r=0.385,P=0.001).进一步分层分析发现EGFR的表达状况影响乳腺癌组织中PI3K和p-PI3K的表达.在EGFR阴性组中,2者表达无明显相关性(r=0.186,P=0.227),而在EGFR阳性组中,2者的表达呈现显著正相关(r =0.396,P=0.001).④PI3K在维、汉不同民族间及不同组织学分级间的表达差异有统计学意义(x2=7.846,P=0.020;x2 =7.160,P=0.028),与肿瘤大小、腋淋巴结转移及肿瘤分期等无关.p-PI3K的表达与各项临床病理特征均无关.结论 乳腺癌的发生过程中,受上游影响因子刺激后,PI3K能被磷酸化激活并发挥信号传导作用.EGFR可能参与激活下游的PI3K信号通路,其表达状况影响PI3K信号通路的激活.在不同亚型乳腺癌中PI3K及其磷酸化蛋白的表达存在差异,各具不同特点,提示可针对不同类型乳腺癌制定不同的个体化策略,PI3K可能成为乳腺癌治疗的新靶点.%Objective To study the differential expression of epidermal growth factor receptor(EGFR),phosphoinositide 3 kinase(PI3K) and its phosphorylated protein p-PI3K,and to analyze the correlation between the expression of the three proteins and clinicopathological features in different subtypes of breast cancer,and to investigate the role of PI3K and its phosphorylated protein p-PI3K in the PI3K/Akt/mTOR signaling pathway in the development and progression of breast cancer.Methods 117 cases of newly diagnosed invasive breast cancer were selected from Jan.2005 to Jun.2010 in Affiliated Cancer Hospital of Xinjiang Medical University,and molecular typing was made by immunohistochemistry results of ER,PR and HER-2,including triple negative breast cancer group(TN group,28 cases),HER-2 over-expression breast cancer group(HER-2 + group,12 cases)and luminal epithelial breast cancer group (Luminal group,77 cases).Immunohistochemistry was used to detect the expressions of PI3 K,p-PI3 K and EGFR in breast carcinoma and its adjacent tissues,and to analyze their expression characteristics in breast cancer and its different subtypes,as well as the correlations between their expressions and clinicopathological features.Results (1) Expressions of PI3K,p-PI3K and EGFR in breast cancer tissues and the adjacent tissues were different:the positive expression rates of PI3K and p-PI3K in breast cancer tissues were higher those that in the adjacent tissues,and the difference had statistical significance (x2 =27.589,P ＜ 0.001 ;x2 =49.327,P ＜ 0.001).EGFR expressions were significantly different in breast cancer tissues and the adjacent tissues(x2 =10.920,P =0.004).(2) Expression of PI3K,p-PI3K and EGFR in different subtypes of breast cancer was different:the positive expression rates of PI3k and p-PI3K were similar between TN group and HER-2 + group,but lower than those in Luminal group,while the expression of EGFR in TN group was significantly higher than those in the other two groups.Expressions of PI3K,p-PI3K and EGFR were statistically different in different subtypes of breast cancer (x2 =9.842,P =0.037 ;x2 =13.423,P =0.006 ;x2 =12.410,P =0.012).Likewise,expressions of PI3K,p-PI3K and EGFR were different between the three different groups (x2 =7.835,P =0.020;x2 =11.791,P =0.003).Expressions of PI3K and EGFR were statistically different only in TN group and Luminal group.There were statistically difference in p-PI3K expression between TN group and Luminal group,and between HER-2 + group and Luminal group(x2 =9.336,P =0.009 ;x2 =7.361,P =0.025).There was no significant difference in the other groups.(3)The correlations of the expressions of PI3 K and p-PI3 K in breast cancer and three different subtypes:compared with PI3K,the positive expression rate of p-PI3K significantly increased in breast cancer,and showed significant positive correlation(r =0.324,P ＜ 0.001).However,this correlation was different between the three different groups.Expressions of PI3k and p-PI3K showed a positive correlation in Luminal group (r =0.385,P =0.001),and there was no relation in TN group and HER-2 group (r =0.222,P =0.257 ; r =0.410,P =0.185).Further stratified analysis showed that the expression status of EGFR affected the expressions of PI3K and p-PI3K in breast cancer.No significant correlation was found in the EGFR negative group(r =0.186,P =0.227),while there was significant positive correlation in EGFR positive group(r =0.396,P =0.001).(4)Relations between expressions of PI3K and p-PI3K and clinicopathological features of breast cancer:there were differences in expressions of PI3K between different ethnic Han and Uighur,as well as between different histological grades (x2 =7.846,P =0.020 ;x2 =7.160,P =0.028),and no correlation with tumor size,axillary lymph node status and tumor staging was found.The expression of p-PI3 K was not related to the clinicopathological features in breast cancer.Conclusions EGFR may play a role in carcinogenesis of breast cancer through activation of the PI3K,and the expression status of EGFR affects the activation of PI3 K signaling pathway.After stimulated by the upstream impact factors,PI3K can be activated and play an important role in the signal transduction pathway.The expressions of PI3K and its phosphorylated proteins p-PI3K are different in different subtypes of breast cancer.The results suggest that individual treatment should be made according to different types of breast cancer,and PI3K may become a new target for breast cancer treatment.
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