14-3-3ζ Overexpression Defines High Risk for Breast Cancer Recurrence and Promotes Cancer Cell Survival

Abstract

The ubiquitously expressed 14-

14-3-3σ stabilizes a complex of soluble actin and intermediate filament to enable breast tumor invasion

“…Intriguingly, 14-3-3ζ has previously been shown to interact with keratins and with actin (46,47), and, like 14-3-3σ ( Fig. 1 and Table S1), 14-3-3ζ expression in breast cancer is associated with poor clinical outcome (48,49). Given the body of literature linking actin-regulatory proteins and BLBC keratins with tumor cell invasion, metastasis, and poor clinical outcome (28,29,34,39,50), we suggest 14-3-3σ regulation of cytoskeletal dynamics may play a fundamental role in BLBC progression to metastatic disease.…”

Targeting 14-3-3zeta in cancer therapy

“…Transient blockade of 14-3-3zeta expression by small interfering RNA (siRNA) in cancer cells effectively reduces the onset and growth of tumor xenografts in vivo. [13][14][15]20,21,27,34,43 In the cancer cells, 14-3-3zeta is commonly associated with some pro-apoptotic proteins upon phosphorylation with survival-mediating kinases, such as Akt. Phosphorylation of 14-3-3zeta by c-Jun N-terminal kinase releases the proapoptotic proteins Bad and FOXO3a from 14-3-3zeta, and antagonizes the effects of Akt signaling.…”

“…13 The importance of 14-3-3zeta in the formation and progression of cancer has been emphasized within several tumor types. [14][15][16][17][18][19][20][21][22][23][24] In this review, we will investigate the role of 14-3-3zeta in cancer and suggest a new target in anticancer therapy.…”

“…19 14-3-3zeta-positive expression occurs in the lung cancer, [25][26][27][28] liver cancer, 21 uterus, breast carcinoma, 14 stomach cancer, 29 head and neck squamous cell carcinoma 15 and so on. In addition, 14-3-3zeta protein expression is elevated in the breast cancer, 14 36 which shows 14-3-3zeta overexpression also occurred in cervical, ovarian, skin, pancreatic, prostate and urothelial tumors. 14-3-3zeta protein also is secreted by tumor-associated monocytes/macrophages from ascites of epithelial ovarian cancer patients.…”

14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma

“…14-3-3σ expression is inhibited in premalignant and malignant cells (5), and loss of 14-3-3σ results in polyploidy and failure to maintain G2/M cell-cycle arrest after DNA damage through cytoplasmic sequestration of CDC2/cyclin B1 (6, 7). 14-3-3ζ expression is up-regulated in various cancers (8), and it induces epithelial-mesenchymal transition by activation of TGF-β/Smads and inhibits apoptosis in anoikic cells, thereby potentiating tumor invasion and metastasis (9,10). Although these observations demonstrate functional roles for altered expression of 14-3-3 in tumorigenesis, there have heretofore been no reported instances of genomically aberrant 14-3-3 oncogenes.…”