Abstract
The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is activated in multiple cancers including ovarian carcinoma (OC). However, the relative contribution of the single components within the PI3K pathway to AKT activation in OC is still unclear. We examined 98 tumor samples from Italian OC patients for alterations in the members of the PI3K pathway. We report that AKT is significantly hyperactive in OC compared to normal tissue (n = 93; p<0.0001) and that AKT activation is preferentially observed in the elderly (>58 years old; n = 93; p<0.05). The most frequent alteration is the overexpression of the p110α catalytic subunit of PI3K (63/93, ∼68%); less frequent alterations comprise the loss of PTEN (24/89, 27%) and the overexpression of AKT1 (18/96, 19%) or AKT2 (11/88,12.5%). Mutations in the PIK3CA or KRAS genes were detected at lower frequency (12% and 10%, respectively) whereas mutations in AKT1 or AKT2 genes were absent. Although many tumors presented a single lesion (28/93, of which 23 overexpressed PIK3CA, 1 overexpressed AKT and 4 had lost PTEN), many OC (35/93) presented multiple alterations within the PI3K pathway. Apparently, aberrant PI3K signalling was mediated by activation of the canonical downstream AKT-dependent mTOR/S6K1/4EBP1 pathway and by regulation of expression of oncogenic transcription factors that include HMGA1, JUN-B, FOS and MYC but not by AKT-independent activation of SGK3. FISH analysis indicated that gene amplification of PIK3CA, AKT1 and AKT2 (but not of PI3KR1) and the loss of PTEN are common and may account for changes in the expression of the corresponding proteins. In conclusion, our results indicate that p110α overexpression represents the most frequent alteration within the PI3K/AKT pathway in OC. However, p110α overexpression may not be sufficient to activate AKT signalling and drive ovarian tumorigenesis since many tumors overexpressing PI3K presented at least one additional alteration.
Highlights
Epithelial ovarian carcinoma (OC) is the most lethal gynecological malignancy with most patients diagnosed only at advanced stages [1,2]
AKT Activation in OC As a read-out of phosphatidylinositol 3-kinase (PI3K)/AKT signalling in OC from Italian patients we determined the phosphorylation status of aminoacid S473 of AKT1. pAKT was evaluated on Tissue Microarray (TMA) containing duplicated core biopsies of 98 OC
AKT activation was observed in 73 out of 93 OC analysed and was significantly higher in cancer samples than in normal controls (Table 1; p,0.0001). pAKT staining was observed in 51/66 Serous Ovarian Carcinomas (S-OC) and in 14/16 Endometrioid Ovarian carcinomas (EOC) (Table 1)
Summary
Epithelial ovarian carcinoma (OC) is the most lethal gynecological malignancy with most patients diagnosed only at advanced stages [1,2]. [3–6] OC is classified by histotype and grade. OC is classified into serous (S-OC), mucinous (M-OC), endometrioid (EOC), clear cell (CC-OC), transitional (or Brenner cancer), squamous cell, and undifferentiated types. S-OC are the most common type of OC, accounting for about two thirds of ovarian carcinomas [7]. Type I lesions constitute 10–20% of OC and include low-grade S-OC, M-OC E-OC, and CC-OC. Low-grade type I cancers present in early stage (I–II), show lowmalignant potential, grow slowly, and are relatively resistant to platinum-based chemotherapy. Type II lesions include high-grade S-OC, and undifferentiated cancers that present at late stage (III–IV), grow more aggressively, though they respond more frequently to platinum-based treatment. The cure rate of patients affected by OC remains low (approximately 30%) the outcome of patients in the late stage has recently improved, with 5-year survival rates approaching 50% [8–10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
