In this study, we predicted and analyzed the impact of three deleterious coding non-synonymous single nucleotide polymorphisms rs121909218 (rs121909218" genes_norm="5728">G129E), rs121909229 (R130Q) and rs57374291 (rs57374291" genes_norm="5728">D107N) in the PTEN gene on the phenotype of breast tumors using computational tools SIFT, Polyphen-2, PROVEAN, MUPro, POPMusic and the GETAREA server.
Recently PTEN/MMAC1, a candidate tumor suppressor gene, was isolated from chromosome 10q23-24 and somatic mutations of this gene were detected in several malignancies including brain, prostate, and breast tumors.
Cowden disease, an autosomal dominant harmartoma syndrome associated with thyroid and breast tumors, has been found to be associated with mutations of PTEN/MMAC1 gene.
The activation of the oncogene PIK3CA and the loss of regulators of AKT including the tumor suppressor gene PTEN are mutations commonly found in breast tumors.
Genotype-phenotype association analyses have revealed that the presence of germline PTEN mutations is associated with breast tumor development, and that mutations occurring within and 5' of the phosphatase motif were associated with multi-organ involvement.
The delivery of exosome containing PTEN-CT to breast tumor mice model was found to result in significant regression in tumor size with the tumor sections showing increased apoptosis.
Together, our data suggest that combined inhibition of HER2 and p110α/β may serve as a potent and durable therapeutic regimen for the treatment of HER2+, PTEN-deficient breast tumors.
In vivo, administering miR-21 antisense oligonucleotides restored trastuzumab sensitivity in the resistant breast cancer xenografts by inducing PTEN expression, whereas injection of miR-21 mimics conferred trastuzumab resistant in the sensitive breast tumors via PTEN silence.
This is the first study to report a differential mechanistic response of tumor-derived and nontumorigenic cell lines and of PTEN high- and low-expressing cells to 13C and indicates a promising chemopreventive role for 13C against estrogen receptor-alpha-negative, aggressive-phenotype breast tumors.