**4. Concluding remarks**

**3.3. P27, a cyclin-dependent kinase inhibitor**

146 Ovarian Cancer - From Pathogenesis to Treatment

cancer management.

mediated degradation of EGFR [84].

Similar to cell-cycle regulatory proteins, cell-cycle inhibitors are frequently altered in cancer [72, 73]. p27Kip1 inhibits cell-cycle G1 phase by interacting with CDK2/cyclin A or CDK2/ cyclin E complexes [73, 74]. Low levels of p27Kip1 protein are associated with tumor progression and growth resulting in poor prognosis of ovarian and breast cancer patients [74–76]. The evaluation of subcellular localization of p27Kip1 in tissue microarray of late-stage ovarian cancer patients revealed that patients with nuclear-only expression of p27Kip1 had a better overall survival than those with negative expression or cytoplasmic localization of the marker (p-value = 0.0002; n = 355) [77]. p27Kip1 level is an important prognostic marker of malignant transformation. Genetically altered mice with p27Kip1 haploinsufficiency are predisposed to cancer [78]. p27Kip1 protein levels are regulated by SCF E3 ligase-associated protein Skp2. Skp2 binds to p27Kip1 and mediates its ubiquitination and subsequent proteasomal degradation [79, 80]. Skp2 levels in different cancers correlate with tumor grade and inversely correlate with p27Kip1 levels and cancer prognosis. Skp2 levels were upregulated in ovarian cancer patients and were associated with advanced FIGO stage III and IV and high grade of the tumor [81]. Skp2 levels were also associated with downregulation of both p27 and p21 in these patients, suggesting an important role of Skp2- p27Kip1 pathway in ovarian cancer pathogenesis. A strong negative correlation between Skp2 levels and FOXO3a (r = −0.743; p < 0.05) in immunohistochemical analysis of ovarian cancer patients indicates that it is another potential target of Skp2 in ovarian cancer [82]. These findings and Skp2 overexpression or amplification in serous ovarian cancer characterize it as an oncogene and its inhibition a plausible approach in ovarian

**3.4. The epidermal growth factor receptor (also known as HER or ERBB) family**

The EGFR family of receptor tyrosine kinases plays an important role in the pathogenesis of several cancers [83]. The four members: EGFR, HER2, HER3, and HER4 (or ERBB1–4), of EGFR family structurally consist of an extracellular ligand-binding domain, a single transmembrane-spanning region, and an intracellular tyrosine kinase domain. More than 30 ligands have been identified that bind to the EGFR family receptors, including EGF- and EGF-like ligands, transforming growth factor (TGF)-α, and heregulins (HRGs) [83]. The activated EGFR receptors undergo C-terminal phosphorylation of cytoplasmic tyrosine residues after receptor dimerization to mediate cell regulatory signaling. E3 ubiquitin ligase CBL binds to EGFR receptor at specific phosphotyrosine residues and mediates its ubiquitination subsequent internalization in clatherin-coated endosomes, which then lead to lysosome-

Amplifications and overexpression of various EGFR family members, including EGFR, Her2, and ErbB3, have been reported in epithelial ovarian cancer. Attenuated ubiquitination and HER2 gene amplification favor the formation of EGFR/HER2 heterodimers that recruit CBL to a lesser degree, thus stabilizing and recycling the receptor to cell surface [85]. BRCA1 mutations are known to be associated with an increased EGFR expression in serous ovarian cancer patients. EGFR expression was not only increased in BRCA1 mutated cancer tissues but was also high in BRCA1-mutated normal tissues compared to respective control tissues. These It is now well known that UPS not only mediates protein degradation but is also involved in the extensive regulation of cellular functions and signaling. A large number of studies in various cancers have uncovered the diverse and intricate role of ubiquitin in oncogenic signaling. The alterations in the genes involved in UPS support its role in cancer development and progression. However, the lack of information on DUBs specificity and multiple targets of E3s raise a question on the use of DUBs or E3s inhibitors in cancer treatment. One possible way forward is to characterize the cancer-specific and tissue-specific expression of DUBs as certain DUBs are predominantly expressed in certain tissues and cancer, suggesting the cancer-specific use of a DUB inhibitor. Moreover, most DUBs studied thus far appear to regulate a small number of targets. It is also possible that only a fraction of ubiquitinated proteins are regulated by a specific DUB family. Similarly, the E3s can be manipulated in cancer if their role is characterized in cancer-specific aberrant molecular signaling. Moreover, further characterization of mutations in DUBs or E3s in cancer patients can be used for cancer screening. In addition, proteasomes carry a great potential in cancer treatment. Although Bortezomib did not show promising results against solid tumors, the advent of next-generation proteasome inhibitors opens new possibilities. Currently, five different types of next-generation proteasome inhibitors are in phase I or phase IIb clinical trials. Moreover, understanding the regulation of proteasomal activity by altered proteasome composition may open novel ways to target proteasomes in cancer.

Compared to breast cancer, ovarian cancer is a rare but far more lethal cancer. It is estimated that 69% of all patients with ovarian carcinoma will succumb to their disease as compared with 19% of those with breast cancer [1]. Ovarian cancer heterogeneity is represented by several genetic (BRCA1/2), epigenetic, and signaling (p53, CDK/p27, CCNE1) alterations, and various UPS components are implicated in these ovarian cancer-specific alterations. Several studies have established a link between UPS and ovarian cancer. However, further studies are needed to identify potential inhibitors for proteasome-based or E3s/DUBs-based therapies in ovarian cancer, which can be taken to clinical trials.
