Significance of Targeting VEGFR-2 and Cyclin D1 in Luminal-A Breast Cancer.

Ashraf N Abdalla,Mohammad Akbar Hossain,Amal Qattan,Imran Shahid,Waleed H Malki,Muhammad Ahmed

doi:10.3390/molecules25204606

Abstract

The hormonal luminal-A is the most pre-dominant sub type of breast cancer (BC), and it is associated with a high level of cyclin D1 in Saudi patients. Tamoxifen is the golden therapy for hormonal BC, but resistance of cancer cells to tamoxifen contributes to the recurrence of BC due to many reasons, including high levels of AIB1 and cyclin D1. Overcoming drug resistance could be achieved by exploring alternative targetable therapeutic pathways and new drugs or combinations. The objective of this study was to determine the differentially enriched pathways in 12 samples of Saudi women diagnosed with luminal-A using the PamChip peptide microarray-based kinase activity profiling, and to compare the activity of HAA2020 and dinaciclib with tamoxifen in singles and combinations in the MCF7 luminal-A cell line. Our results of network and pathway analysis of the 12 samples highlighted the importance of VEGFR and CDKs in promoting luminal-A breast cancer. The activation of VEGF signaling via VEGFR-2 leads to activation of PI3K/AKT kinases and an increase of cell survival, and leads to activation of Hsp90, which induces the phosphorylation of FAK1, resulting in cytoskeleton remodeling. PLC-gamma 1 is also activated, leading to FAK-2 and PKC activation. Notably, the G1/S cell cycle phases and phosphorylation processes contribute to the top seven tumorigenesis processes in the 12 samples. Further, the MTT combination of HAA2020 and dinaciclib showed the best combination index (CI), was more clonogenic against MCF7 cells compared to the other combinations, and it also showed the best selectivity index (SI) in normal MRC5 cells. Interestingly, HAA2020 and dinaciclib showed a synergistic apoptotic and G1 cell cycle effect in MCF7 cells, which was supported by their synergistic CDK2, cyclin D1, and PCNA inhibition activities. Additionally, the combination showed VEGFR-2 and Hsp90 inhibition activities in MCF7 cells. The results show the significance of targeting VEGFR-2 and cyclin D1 in Saudi luminal-A breast cancer patients, and the effect of combining HAA2020 and dinaciclib on those targets in the MCF7 model. It also warrants further preclinical and in vivo investigations for the combination of HAA2020 and dinaciclib as a possible future second-line treatment for luminal-A breast cancers.

Highlights

Breast cancer (BC) is a global health challenge
Most of the clinical sample characteristics under study were similar to the characteristics of previous Saudi studies [4,5], as 50% of the samples were from pre-menopausal patients, and 66% and 34% were grade II and III, respectively
83% were ductal vs. 17% lobular samples

Summary

Introduction

Breast cancer (BC) is a global health challenge. With 11.6% of the total diagnosed cancer cases in 2018 in 185 countries, it remains the number one malignancy in females [1]. In Saudi Arabia, it is the top female malignancy in all ages, reaching 28.7% in 2014 [2], which is more than double the average global incidence percentage. BC comprises four sub-types, determined by the hormone receptor (HR). Human epidermal growth factor receptor 2 (Her). Is the most dominant, which affected more than 73% of the total BC patients in the US alone during. In a study of 359 Saudi BC patients, luminal-A cases showed the highest percentage (58.5%). Similar characterization studies in different countries revealed variation of the luminal-A percentage. An average of 34.7% was reported in Oman, 69% in Poland, and 47.4%

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Results

Conclusion