Downregulation of Alpha‐L‐Fucosidase Expression Is Related to Dedifferentiation and Worse Prognosis in Thyroid and Breast Cancer.
Authors: Vecchio Giancarlo , Parascandolo Alessia , Allocca Chiara , Ugolini Clara , Basolo Fulvio , Bonin Serena , Stanta Giorgio , Castellone Maria Domenica , Santoro Massimo , Tsuchida Nobuo 
Published: November 2023

It has been reported that α‐L‐Fucose participates in several interaction processes between cells and between cells and extracellular matrix. It has also been reported that high levels of fucose are related to neoplastic progression. The lysosomal enzyme α‐L‐Fucosidase‐1 (FUCA‐1) is involved in the removal of fucose from glycans. The FUCA‐1 gene has recently been shown to be down‐regulated in highly aggressive and metastatic histotypes of human tumors. It is speculated that its inactivation perturbs the glycosylation of proteins involved in cell adhesion, migration and metastases. We have analyzed the expression of the FUCA‐1 gene in two different types of human cancers, i.e., thyroid and breast cancer and have studied the correlation between the expression of the gene and: a) Degree of differentiation and aggressiveness of the different thyroid cancer histotypes; b) Recurrences and cancer specific survival in a cohort of breast cancer patients with and without lymph node involvement. We have compared by qRT‐PCR the expression of FUCA‐1 mRNA in 15 papillary (PTC), 10 anaplastic (ATC) thyroid cancer biopsies and 6 biopsies from non tumoral thyroid tissues. Furthermore, we have analyzed by immunohistochemistry (IHC) using a polyclonal anti‐FUCA‐1 antibody, formalin‐fixed and paraffin‐embedded biopsies consisting of 34 cases of PTC, 23 poorly differentiated (PDC), 33 ATC and 12 cases of normal thyroid tissues. We have then analyzed FUCA‐1 expression with the same antibody in 4 tissue microarrays including 305 breast cancer specimens. Fifty percent of those breast cancer patients presented at diagnosis with lymph node involvement (LN+) and 50% without (LN−). Finally we have analyzed FUCA‐1 expression by qRT‐PCR and Western blot (WB) analysis of continuous cell lines derived either form differentiated (PTC) or undifferentiated (ATC) thyroid cancer and from well differentiated (luminal A) or undifferentiated (triple negative) breast cancer. We have found that FUCA‐1 mRNA expression was decreased to about half in ATC with respect to PTC and normal thyroid biopsies. Furthermore, the expression of FUCA‐1 as determined by IHC, decreased progressively and significantly from PTC, through PDC to ATC. Moreover, negativity to FUCA‐1 was significantly related to the development of later recurrences in breast cancer patients with lymph node involvement at diagnosis, as 68% of recurrent woman were negative to FUCA‐1 compared to 47% of non recurrent ones. Furthermore, survival of luminal B LN+ patients was influenced by FUCA‐1 expression since luminal B LN+ patients with positive expression had a longer specific survival. Finally, the continuous cell line derived from an ATC (8505c) displayed lower FUCA‐1 expression by either qRT‐PCR or by WB analysis, with respect to more differentiated PTC‐derived (TPC1) cancer cell line. The down regulation of FUCA‐1, therefore, correlates with increased aggressiveness in thyroid cancers and with a worse prognosis in women with breast cancer.

Support or Funding Information

Work partly supported by PON01_02782, Ministero dell'Istruzione, dell'Università e della Ricerca, Italy, to Istituto Superiore di Oncologia.