PTEN mutations have been implicated in the development of a variety of human neoplasia, including high-grade glioblastoma, prostate, breast, endometrial, and thyroid carcinoma.
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).
A total of 32 of 225 PTEN mutation+ patients (14%) had thyroid cancer: 52% papillary, 28% follicular-variant papillary, 14% follicular, and 6% anaplastic.
After co-culture with TC cell lines, TC-induced macrophages showed significantly increased production of cytokines in both patients and controls, especially after co-culture with a PTEN-deficient TC cell line; these effects were abolished after use of rapamycin or a lactate transport blocker.
Because in most of the thyroid carcinomas, DeltaNp73alpha is upregulated, whereas PTEN expression down regulated, we investigated whether DeltaNp73alpha may influence PTEN expression in this cell model.
Germline PTEN mutations cause 85% of Cowden syndrome (CS), characterized by a high risk of breast and thyroid cancers, and 65% of Bannayan-Riley-Ruvalcaba syndrome (BRRS), characterized by lipomatosis, hemangiomas and speckled penis.
Germline mutations in PTEN, encoding a dual-specificity phosphatase on 10q23.3, cause Cowden syndrome (CS), which is characterized by a high risk of breast and thyroid cancers.
Germline mutations in the PTEN gene, which cause Cowden syndrome, are known to be one of the genetic factors for primary thyroid and breast cancers; however, PTEN mutations are found in only a small subset of research participants with non-syndrome breast and thyroid cancers.
Germline variants in SDHB/C/D (SDHx) genes account for subsets of CS/CS-like cases, conferring a higher risk of breast and thyroid cancers over those with only germline PTEN mutations.
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.
In this study, we confirm that PTEN mutations in sporadic thyroid cancer are infrequent as we found one point mutation and one heterozygous deletion of PTEN gene in 26 tumors and eight cell lines screened.
Moreover, germline mutation of PTEN leads to the development of the related hereditary cancer predisposition syndromes, Cowden disease, and Bannayan-Zonana syndrome, wherein breast and thyroid cancer incidence is elevated.