Abstract
The calcium (Ca2+)-dependent membrane-binding Annexin A6 (AnxA6), is a multifunctional, predominantly intracellular scaffolding protein, now known to play relevant roles in different cancer types through diverse, often cell-type-specific mechanisms. AnxA6 is differentially expressed in various stages/subtypes of several cancers, and its expression in certain tumor cells is also induced by a variety of pharmacological drugs. Together with the secretion of AnxA6 as a component of extracellular vesicles, this suggests that AnxA6 mediates distinct tumor progression patterns via extracellular and/or intracellular activities. Although it lacks enzymatic activity, some of the AnxA6-mediated functions involving membrane, nucleotide and cholesterol binding as well as the scaffolding of specific proteins or multifactorial protein complexes, suggest its potential utility in the diagnosis, prognosis and therapeutic strategies for various cancers. In breast cancer, the low AnxA6 expression levels in the more aggressive basal-like triple-negative breast cancer (TNBC) subtype correlate with its tumor suppressor activity and the poor overall survival of basal-like TNBC patients. In this review, we highlight the potential tumor suppressor function of AnxA6 in TNBC progression and metastasis, the relevance of AnxA6 in the diagnosis and prognosis of several cancers and discuss the concept of therapy-induced expression of AnxA6 as a novel mechanism for acquired resistance of TNBC to tyrosine kinase inhibitors.
Highlights
Breast cancer is the most common cancer among women in the USA, with an incidence of63,410 cases of in situ disease, 268,600 new cases of invasive disease, and 41,760 deaths estimated in 2019 [1]
Annexin A6 (AnxA6) mutant led to diminished GTP binding and GTP-induced ion channel activity, and the formation of AnxA6 trimers in the presence of GTP [50]. This notwithstanding and given that nucleotides are required for the activation of protein kinases and small GTPases, it is plausible to suggest that the nucleotide-binding characteristic of AnxA6 contributes to cellular functions related to tumorigenesis, endocytosis, exocytosis, vesicular transport and signal transduction pathways
These multiple cellular activities driven by the interaction of AnxA6 with S100 proteins could be critical for the organization of membrane microdomains including lipid rafts, focal adhesions and cell–cell contacts, which independently contribute to enhanced cell motility
Summary
Breast cancer is the most common cancer among women in the USA, with an incidence of. TKIs such as lapatinib, erlotinib, gefitinib, as well as the more recent generations of these drugs, block the kinase activity of the receptor by competing with ATP binding to the ATP binding pocket in the cytosolic tyrosine kinase domain of the receptor [14] Some of these TKIs have been approved for the treatment of TNBC, while others are approved for other cancer types, and inhibit tumor growth by promoting cell cycle arrest and apoptosis [15]. We will discuss the novel concept of therapy-induced upregulation of AnxA6 especially in basal-like TNBC cells with low AnxA6 levels (AnxA6-low TNBC cells) as another mechanism for acquired resistance of this hard-to-treat breast cancer subtype to TKIs
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