Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Trastuzumab Modulates the Protein Cargo of Extracellular Vesicles Released by ERBB2+ Breast Cancer Cells

Version 1 : Received: 22 February 2021 / Approved: 24 February 2021 / Online: 24 February 2021 (11:38:41 CET)

A peer-reviewed article of this Preprint also exists.

Marconi, S.; Santamaria, S.; Bartolucci, M.; Stigliani, S.; Aiello, C.; Gagliani, M.C.; Bellese, G.; Petretto, A.; Cortese, K.; Castagnola, P. Trastuzumab Modulates the Protein Cargo of Extracellular Vesicles Released by ERBB2+ Breast Cancer Cells. Membranes 2021, 11, 199. Marconi, S.; Santamaria, S.; Bartolucci, M.; Stigliani, S.; Aiello, C.; Gagliani, M.C.; Bellese, G.; Petretto, A.; Cortese, K.; Castagnola, P. Trastuzumab Modulates the Protein Cargo of Extracellular Vesicles Released by ERBB2+ Breast Cancer Cells. Membranes 2021, 11, 199.

Journal reference: Membranes 2021, 11, 199
DOI: 10.3390/membranes11030199

Abstract

Cancers overexpressing the ERBB2 oncogene are aggressive and associated with a poor prognosis. Trastuzumab is a ERBB2 specific recombinant antibody employed for the treatment of these diseases since it blocks ERBB2 signaling causing growth arrest and survival inhibition. While the effects of Trastuzumab on ERBB2 cancer cells are well known, those on the extracellular vesicles released from these cells are scarce. This study focused on ERBB2+ breast cancer cells and aimed to establish what type of EVs they release and whether Trastuzumab affects their morphology and molecular composition. To these aims, we performed immunoelectron microscopy, immunoblot, and high-resolution mass spectrometry analyses on EVs purified by differential centrifugation of culture supernatant. Here we show that EVs released from ERBB2+ breast cancer cells are polymorphic in size and appearance, and that ERBB2 is preferentially associated with large (120 nm) EVs. Moreover, we report that Tz induces the expression of a specific glycosylated 50 kDa isoform of the CD63 tetraspanin and modulates the expression of 51 EVs proteins, including TOP1. As these proteins are functionally associated with organelle organization, cytokinesis, and response to lipids, we suggest that Tz may influence these cellular processes in target cells at distant sites via modified EVs.

Subject Areas

trastuzumab, HER2, extracellular vesicles, breast cancer, proteomic analysis, immunoelectron microscopy, TOP1, CD63, mitochondria.

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