mRNA expression of delta-HER2 and its clinicopathological correlation in HER2-overexpressing breast cancer

Delta-human epidermal growth factor receptor 2 (HER2) is a splice variant of HER2, which lacks 16 amino acids in the extracellular domain. The aim of the present study was to elucidate the expression of delta-HER2 and its clinicopathological correlation in Japanese patients with HER2-overexpressing breast cancer. A total of 40 cases of HER2-overexpressing breast cancer were investigated. The mRNA expression levels of wild type (wt)-HER2 and delta-HER2 were quantitated by quantitative polymerase chain reaction using RNA extracted from formalin-fixed paraffin-embedded specimens. In addition, the activated form of phosphorylated-SRC (pSRC) and Ki-67 were detected by immunostaining. The mRNA expression levels of wt-HER2 varied largely, and the mRNA levels of delta-HER2 were correlated with those of wt-HER2. Furthermore, the enhanced immunostaining of pSRC was detected in 15 cases. Unsupervised hierarchal clustering of wt-HER2, delta-HER2 and pSRC was used to separate the cases into three clusters. In the first cluster, the levels of wt-HER2 and delta-HER2 were low, and pSRC immunostaining was low. Two other clusters were characterized by moderately and highly increased levels of wt-HER2 and delta-HER2 mRNA expression and enhanced pSRC. The delta/wt ratio was higher in the first cluster. Positive lymph node status and recurrence were more frequent in the first cluster compared with those in the two other clusters. Furthermore, the delta/wt ratio was significantly increased in lymph node-positive and recurrent cases, compared with in lymph node-negative and non-recurrent cases. The present study demonstrated that delta-HER2 was expressed in Japanese patients with HER2-overexpressing breast cancer. High mRNA expression levels of delta-HER2 were associated with pSRC and increased proliferation of tumor cells. A poor prognosis may be predicted by the increase in delta/wt ratio in HER2-overexpressing breast cancer.