Abstract
IntroductionBreast cancer is the most common female malignancy worldwide and, despite improvements in treatment modalities, there are increased chances of recurrence and metastasis in a substantial number of cases and it remains one of the major causes of mortality among female cancer patients. Anaplastic lymphoma kinase (ALK) gene has been found to be altered in several solid and hematologic tumors. We aimed to comprehensively study the prevalence of ALK expression, and changes in copy number and translocation in a large cohort of breast cancer cases in a Middle Eastern population.MethodsALK protein expression was investigated by immunohistochemistry and numerical and structural variations of the ALK gene were analyzed by fluorescence in situ hybridization (FISH) in a tissue microarray format in a cohort of more than 1000 Middle Eastern breast cancers. The data were correlated with clinicopathologic parameters and other important molecular biomarkers.ResultsImmunohistochemical analysis showed ALK overexpression in 36.0 % of the breast cancer patients and gene amplification was present in 13.3 % of cases, seen by FISH analyses. ALK overexpression was significantly associated with ALK gene amplification (p = 0.0031). ALK-overexpressing tumors showed significant association with high-grade tumors (p = 0.0039), ductal histologic subtype (p = 0.0076), triple-negative phenotype (p = 0.0034), and high Ki-67 (p = 0.0001) and p-AKT (p <0.0001).ConclusionsImmunohistochemical analysis showed ALK is overexpressed in a substantial proportion of breast cancers and possibly plays a significant role in the aggressive behavior of this cancer. Gene amplification is hypothesized to be a possible cause for a significant proportion of this overexpression. Based on these findings, a potential role for an ALK inhibitor, as a therapeutic agent targeting aggressive subtypes of breast cancer, merits further investigation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0610-3) contains supplementary material, which is available to authorized users.
Highlights
Breast cancer is the most common female malignancy worldwide and, despite improvements in treatment modalities, there are increased chances of recurrence and metastasis in a substantial number of cases and it remains one of the major causes of mortality among female cancer patients
We examined the association of triple-negative breast cancers (TNBC) with clinicopathologic parameters, biomarker expression and performed survival analysis
Anaplastic lymphoma kinase (ALK) overexpression was seen in 36 % of Middle Eastern breast cancer cases and this observation is in concordance with an earlier published study showing 47 % of ALK overexpression in a cohort of 100 breast cancer cases [45]
Summary
Breast cancer is the most common female malignancy worldwide and, despite improvements in treatment modalities, there are increased chances of recurrence and metastasis in a substantial number of cases and it remains one of the major causes of mortality among female cancer patients. Approximately 1.5 million women around the world are diagnosed with breast cancer [2]. It is the most common malignancy diagnosed among Saudi females [3] and is found to have an advanced stage, high grade and tends. ALK has been reported to be translocated with other fusion partners, such as KIF5B [8], NPM1 [7], RET, ROS [9], VCL [10], TFG [11], EML4 [12] and MYH9, demonstrating its role in the pathogenesis of various cancers. The. Siraj et al Breast Cancer Research (2015) 17:127 chimeric protein resulting from the fusion has lead to constitutively activated ALK tyrosine kinase [9, 10, 13]. It has been demonstrated that inhibition of ALK inhibits growth of breast cancer cell lines and tumor xenografts in mouse models [21]
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