EHD2 overexpression promotes tumorigenesis and metastasis in triple-negative breast cancer by regulating store-operated calcium entry

Luan, H.; Bielecki, T. A.; Mohapatra, B. C.; Islam, N.; Mushtaq, I.; Bhat, A. M.; Mirza, S.; Chakraborty, S.; Raza, M.; Storck, M. D.; Meza, J. L.; Thoreson, W. B.; Coulter, D. W.; Rakha, E.; Band, V.; Band, H.

doi:10.1101/2022.06.21.497035

bioRxiv · 10.1101/2022.06.21.497035

EHD2 overexpression promotes tumorigenesis and metastasis in triple-negative breast cancer by regulating store-operated calcium entry

Luan, H.·Bielecki, T. A.·Mohapatra, B. C.·Islam, N.·Mushtaq, I.·Bhat, A. M.·Mirza, S.·Chakraborty, S.·Raza, M.·Storck, M. D.·Meza, J. L.·Thoreson, W. B.·Coulter, D. W.·Rakha, E.·Band, V.·Band, H.

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Abstract

With nearly all cancer deaths a result of metastasis, elucidating novel pro-metastatic cellular adaptations could provide new therapeutic targets. Here, we show that overexpression of the EPS15-Homology Domain-containing 2 (EHD2) protein in a large subset of breast cancers (BCs), especially the triple-negative (TNBC) and HER2+ subtypes, correlates with shorter patient survival. The mRNAs for EHD2 and Caveolin-1/2, structural components of caveolae, show co-overexpression across breast tumors, predicting shorter survival in basal-like BC. EHD2 shRNA knockdown and CRISPR-Cas9 knockout of EHD2, together with mouse EHD2 rescue, in TNBC cell line models demonstrate a major positive role of EHD2 in promoting tumorigenesis and metastasis. Mechanistically, we link these roles of EHD2 to store-operated calcium entry (SOCE), with EHD2-dependent stabilization of plasma membrane caveolae ensuring high cell surface expression of the SOCE-linked calcium channel Orai1. The novel EHD2-SOCE oncogenic axis represents a potential therapeutic target in EHD2 and CAV1/2-overexpressing BC.

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Luan, H., Bielecki, T. A., Mohapatra, B. C., Islam, N., Mushtaq, I., Bhat, A. M., Mirza, S., Chakraborty, S., Raza, M., Storck, M. D., Meza, J. L., Thoreson, W. B., Coulter, D. W., Rakha, E., Band, V., Band, H.. 2022-06-25. EHD2 overexpression promotes tumorigenesis and metastasis in triple-negative breast cancer by regulating store-operated calcium entry. https://doi.org/10.1101/2022.06.21.497035

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