Abstract P4-05-03: Heat shock protein 27 (HSP27) and HER2 positively correlate in breast cancer and effect cell responsiveness to neratinib and cMET inhibitor
Authors: Owen S , Sanders AJ , Ruge F , Lalani AS , Avogadri-Connors F , Bryce RP , Jiang WG 
Published: February 2018

Background: Upregulation of heat shock protein-27 (HSP27), a key member of the HSP family, has been shown to confer resistance to chemotherapy and radiotherapy in solid tumours including breast cancer. Evidence is also emerging that HSP27 is linked to the metastatic spread of breast cancer and key cellular traits including cellular migration. Neratinib is an orally available tyrosine kinase inhibitor that irreversibly binds and inhibits EGFR, HER2 and HER4 receptor tyrosine kinases. cMET, the receptor for hepatocyte growth factor and target for cancer therapies, has been shown to be trans-phosphorylated by EGFR. In the current study, we evaluated HSP27 expression within a breast cancer cohort and its implications in cellular responsiveness to cMET inhibition and neratinib.

Methods: HSP27 transcript expression was analysed in our chemotherapy naïve breast cancer cohort (n=124) using quantitative PCR (qPCR) and compared to clinic-pathological information including long-term survival over a ten year follow up period. In addition, the correlation between HSP27 and HER2 expression was explored using Spearman Rank order. High-throughput cell migration analysis was performed using ECIS, on MCF-7 control and HSP27 siRNA knockdown cells in conjunction with neratinib and PHA 665752, a small molecule cMET inhibitor.

Results: In our primary breast cancer cohort, there were no significant associations between HSP27 transcript expression levels and tumour grade, TNM or estrogen receptor (ER) status. Combined survival expression analysis indicated that the worst patient prognosis was associated with high levels of both HER2 and HSP27 and high HER2 and low HSP27 whereas best patient prognosis was associated with low HER2 and low HSP27 expression. Knockdown of HSP27 in MCF7 cells brought about a reduction in cellular migration compared to the control. Additionally, this reduction was enhanced by the addition of neratinib, in a concentration dependent manner, and also cMET inhibition when individually treated. Furthermore, the greatest inhibitory effects on MCF-7 migration were seen following HSP27 knockdown and combined treatment with neratinib and PHA 665752.

Conclusions: Our current data suggests that HSP27 confers low sensitivity to drugs such as neratinib and PHA 665752, particularly in relation to cellular migration and hence potentially metastasis. Therefore, the targeting of HSP27, HER2 and cMET appear to act syngeristically to regulate cellular migration in vitro. Furthermore, clinically expression of HER2 and HSP27 may serve as a prognostic marker for breast cancer survival. Hence, combination therapies that target both HSP and HER2 pathways may provide new clinical opportunities for preventing breast cancer progression.

Citation Format: Owen S, Sanders AJ, Ruge F, Lalani AS, Avogadri-Connors F, Bryce RP, Jiang WG. Heat shock protein 27 (HSP27) and HER2 positively correlate in breast cancer and effect cell responsiveness to neratinib and cMET inhibitor [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-05-03.