Dysregulation of the PI3K/AKT/mTOR Pathway in Breast Cancer and its Manipulation as Potential for Treatment
Introduction. Breast cancer is a disease in which the cells of the breast proliferate uncontrollably and is categorized into subtypes depending on the presence or absence of cell surface estrogen receptors (ER), progesterone receptors (PR), or human epidermal growth factor 2 (HER2).1 It is the most common cancer in females.2,3 Prognosis is determined by cell surface receptor subtype, with triple-negative phenotype harboring the worst prognosis, and progression toward metastasis to distant tissues.1 Genetic and environmental factors are implicated in breast cancer incidence, including inherited dysfunctional genes or acquired conditions like obesity.2 Dysregulation of the PI3K/AKT/mTOR pathway may lead to breast cancer, and its components may be exploited to develop additional insight, preventative measures, and effective treatment for breast cancer. Methods. PTEN-loss was examined through PTEN immunohistochemistry of biopsies obtained from early breast cancer patients and graded as “PTEN-loss” or “PTEN-no-loss” by pathologists based on intensity of staining.4 The resultant “PTEN-loss” and “PTEN-no-loss” status was then correlated with subtype of cancer.4 Furthermore, cell lysates from cell lines containing E545K mutation of PI3K, multi-drug resistant phenotype, and mTOR mutation in the focal adhesion kinase targeting domain were western-blotted and the resultant intensities of pro-growth cell markers such as phosphorylated AKT, mTOR, and S6K were compared to western blots of wild type cell lysates.7,8,9 Results. Patients with PTEN-loss phenotype demonstrated high-risk breast cancer phenotypes.4 In western blots of cell lines containing the E545K mutation in PI3K, it was noted that the intensities of phosphorylated AKT and phosphorylated mTOR were greater than wild-type cell lines.5 Moreover, western blots obtained from multi-drug resistant cancer cell lines noted higher intensities of phosphorylated AKT and phosphorylated PTEN, correlating with increased cell viability and reduced apoptosis.6 Lastly, mutations in the mTOR focal adhesion kinase targeting domain led to higher cellular loads of phosphorylated S6K verified by western blot, which correlated with increased protein synthesis and cellular viability.7 Conclusion. Studies indicate that cells harboring dysregulated PI3K/AKT/mTOR pathway are correlated with highly proliferative phenotype and are implicated in breast cancer. Insight into this pathway may also elucidated various novel methods for treatment. For example, BELLE-3, a randomized/double-blinded/placebo-controlled phase III clinical trial noted that buparlisib, a mTOR inhibitor, showed a modest increase in overall survival of patients with local or metastatic breast cancer compared with a control group.8 Further research into the pathway may therefore yield better treatments in the future.
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- Leo AD, Johnston S, Lee KS, et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology. 2018;19(1):87-100. doi:10.1016/s1470-2045(17)30688-5