Diva S. Whalen

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.

Fetuin-A is the protein product of the AHSG gene in humans. It is mainly synthesized by the liver in adult humans and is secreted into the blood where its concentration can vary from a low of ~0.2 mg/mL to a high of ~0.8 mg/mL. Presently, it is considered to be a multifunctional protein that plays important roles in diabetes, kidney disease, and cancer, as well as in inhibition of ectopic calcification. In this review we have focused on work that has been done regarding its potential role(s) in tumor progression and sequelae of diabetes. Recently a number of laboratories have demonstrated that a subset of tumor cells such as pancreatic, prostate and glioblastoma multiform synthesize ectopic fetuin-A, which drives their progression. Fetuin-A that is synthesized, modified, and secreted by tumor cells may be more relevant in understanding the pathophysiological role of this enigmatic protein in tumors, as opposed to the relatively high serum concentrations of the liver derived protein. Lastly, auto-antibodies to fetuin-A frequently appear in the sera of tumor patients that could be useful as biomarkers for early diagnosis. In diabetes, solid experimental evidence shows that fetuin-A binds the β-subunit of the insulin receptor to attenuate insulin signaling, thereby contributing to insulin resistance in type 2 diabetes mellitus (T2DM). Fetuin-A also may, together with free fatty acids, induce apoptotic signals in the beta islets cells of the pancreas, reducing the secretion of insulin and further exacerbating T2DM.