PTEN, a dual-phosphatase tumor suppressor, is inactivated in Cowden syndrome (CS), characterized by high risk of breast and thyroid cancer, and in variety of sporadic cancers.
PTEN knockdown in thyroid cancer cell lines stabilized intracellular NIS protein by promoting an interaction with NIS-LARG (leukemia-associated RhoA guanine exchange factor).
Notably, individuals with SDH(var+) alone had the highest thyroid cancer prevalence (24/47) compared with PTEN(mut+) patients (27/105, P = 0.002) or PTEN(mut+)/SDH(var+) carriers (6/22, P = 0.038).
PPFP thyroid cancers have increased activation of AKT, and mice with thyroid-specific expression of PPFP combined with thyroid-specific loss of PTEN (a negative regulator of AKT) develop thyroid cancer.
We show that SRC inhibition could rescue SDHD dysfunction-induced cellular phenotype and tumorigenesis only when wild-type PTEN is expressed, in thyroid cancer lines.
In conclusion, our data define a novel mechanism of PI3K/AKT hyperactivation and outline a regulatory role for miR-146b in suppressing PTEN expression, a frequent observation in thyroid cancer.
Our study shows that low blood PTEN protein expression could serve as a screening molecular correlate to predict for germline PTEN mutation in CS and CS-like presentations of thyroid cancer.
Whereas PTEN inactivation is uncommon in sporadic thyroid cancer, activation of growth factor pathways that signal through Akt is frequently identified.