High expression of integrin β6 in association with the Rho-Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers.
High expression of integrin β6 in association with the Rho-Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers.
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DOI：
10.1002/cam4.756
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发表时间：
2016-08
期刊：
影响因子：
4
通讯作者：
Sridhar TS
中科院分区：
文献类型：
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作者：
Desai K;Nair MG;Prabhu JS;Vinod A;Korlimarla A;Rajarajan S;Aiyappa R;Kaluve RS;Alexander A;Hari PS;Mukherjee G;Kumar RV;Manjunath S;Correa M;Srinath BS;Patil S;Prasad MS;Gopinath KS;Rao RN;Violette SM;Weinreb PH;Sridhar TS
整合素αvβ6参与了乳腺导管原位癌向浸润性导管癌的转化过程。此外，整合素β6对浸润性乳腺癌，尤其是HER2+亚型乳腺癌有预后价值。然而，在浸润性乳腺癌的临床进展中，介导整合素αvβ6活性的途径还有待进一步阐明。我们用定量聚合酶链式反应检测了人乳腺癌组织中整合素β6(ITGB6)基因的表达。此外，我们还用免疫组织化学方法检测了α-v-β-6整合素的表达。通过定量聚合酶链式反应(QPCR)检测HER2+亚群中Rho-RAC通路成员的表达水平，包括下游基因(ACTR2、ACTR3)和效应蛋白(MMP9、MMP15)。在HER2+肿瘤中，ITGB6的平均表达明显高于HR+HER2-和三重阴性(TNBC)亚型(P=0.00)。HER2+肿瘤中ITGB6表达水平最高(上四分位数)，Rho-Rac途径的所有基因水平均显著升高(P值从0.01%到0.0001)。与ITGB6水平较低的组相比，该组患者的无病生存期明显缩短(HR=22.9(0.9-8.9)，P=00.05)。在淋巴结阳性的肿瘤中，ITGB6的平均表达水平进一步升高。高表达ITGB6的HER2+肿瘤的局部和远处转移增加可能是通过MMP9和MMP15表达增加的典型的Rho-Rac途径介导的。
Integrin αvβ6 is involved in the transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast. In addition, integrin β6 (ITGB6) is of prognostic value in invasive breast cancers, particularly in HER2+ subtype. However, pathways mediating the activity of integrin αvβ6 in clinical progression of invasive breast cancers need further elucidation. We have examined human breast cancer specimens (N = 460) for the expression of integrin β6 (ITGB6) mRNA by qPCR. In addition, we have examined a subset (N = 147) for the expression of αvβ6 integrin by immunohistochemistry (IHC). The expression levels of members of Rho–Rac pathway including downstream genes (ACTR2,ACTR3) and effector proteinases (MMP9,MMP15) were estimated by qPCR in the HER2+ subset (N = 59). There is a significant increase in the mean expression of ITGB6 in HER2+ tumors compared to HR+HER2‐ and triple negative (TNBC) subtypes (P = 0.00). HER2+ tumors with the highest levels (top quartile) of ITGB6 have significantly elevated levels of all the genes of the Rho–Rac pathway (P‐values from 0.01 to 0.0001). Patients in this group have a significantly shorter disease‐free survival compared to the group with lower ITGB6 levels (HR = 2.9 (0.9–8.9), P = 0.05). The mean level of ITGB6 expression is increased further in lymph node‐positive tumors. The increased regional and distant metastasis observed in HER2+ tumors with high levels of ITGB6 might be mediated by the canonical Rho–Rac pathway through increased expression of MMP9 and MMP15.