The role of PTEN and its signalling pathways, including AKT, in breast cancer; an assessment of relationships with other prognostic factors and with outcome

Abstract

PTEN is a novel tumour suppressor gene located on chromosome 10. PTEN mutations are believed to exert their effects through the putative PI3K-AKT-mTOR signalling pathway. Specifically, loss of PTEN leads to activation of AKT, which in turn promotes anti-apoptotic and pro-cell cycle entry pathways believed to be essential in tumourigenesis. Whilst PTEN mutations are frequent in a variety of sporadic cancers and inherited cancer syndromes, it is not clear how frequently PTEN mutations and immunohistochemical loss of PTEN expression occur in sporadic breast cancer. This study used tissue microarrays (TMAs) to assess wild-type PTEN and pAKT immunohistochemical staining in 670 and 691 cases, respectively, of primary operable breast cancer. Scores of 0, 1, and 2 were given for negative, weakly positive, and strongly positive degrees of immunoreactivity, respectively. In addition, immunohistochemical assessment of epidermal growth factor receptor (EGFR), Her2, and proliferation by MIB1 expression was performed on the same TMAs and the scores were compared with those of PTEN and pAKT. Eight per cent of cases did not express wild-type PTEN. No correlation was observed between patient, tumour and outcome variables and PTEN. pAKT expression correlated inversely with adverse tumour variables such as tumour grade (p< 0.001) and correlated positively with ER status (p< 0.001). No correlation was seen between either PTEN or AKT and EGFR, Her2 or MIB1. No association of PTEN or pAKT was seen in Kaplan-Meier or multivariate analysis for overall survival. The results indicate that loss of PTEN expression is infrequent in breast cancer. PTEN and AKT do not appear to be prognostic markers. The study argues against the current model of a simple linear tumourigenic PTEN-PI3K-AKT-mTOR pathway in breast cancer. It also suggests that, in this group of breast cancers, the most common upstream regulator of AKT may be ER rather than PTEN, EGFR or Her2.

The Akt pathway in human breast cancer: a tissue-array-based analysis

“…24 We did not observe any relation between PTEN loss and Akt overexpression. A similar finding has been observed by Panigrahi et al, 25 who, in a study of 670 cases of operable invasive breast cancers, found no correlation between the two. Additionally, it is known that PTEN plays a role in increasing cell motility and spreading by regulating the Rho family GTPases (Rho, Rac1, and Cdc42), which in turn regulate the actin cytoskeleton that is directly responsible for cell motility.…”

Immunohistochemical heterogeneity of breast carcinomas negative for estrogen receptors, progesterone receptors and Her2/neu (basal-like breast carcinomas)

“…57 Loss of 51,56 as in our series where Akt, present in 28% of tumors, was more frequently associated with growth factor receptors than with the PTEN pathway. 52,57 Recently, pAkt overexpression was described in 33% of in situ and 38% of ductal invasive breast carcinomas, although without any significant clinicopathological relationship, 56 as in our cases. In summary, Ki67 and p53 are higher in basal than in conventional breast carcinomas.…”

“…50 Lack of PTEN is found in 8-48% of breast carcinomas and is generally associated with a high grade, necrosis, node metastasis and absence of ER. [51][52][53][54][55][56] Generally, PTEN absence in breast carcinomas is due to gene promoter hypermethylation [51][52][53][54][55] or loss of heterozygosity, 53 whereas PTEN mutations are exceptional in sporadic neoplasms. 57 Loss of 51,56 as in our series where Akt, present in 28% of tumors, was more frequently associated with growth factor receptors than with the PTEN pathway.…”

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas

“…43 In a report regarding non-small cell lung cancer by Yoshizawa et al, 23 there was a lack of association between p-AKT1 and p-MTOR expression. It is striking that Panigrahi et al 44 found that the level of PTEN expression was even positively correlated with the level of the p-AKT1 expression in breast cancer. Moreover, RPS6KB2 and eIF4E can be activated by pathways that are independent of MTOR, including the Ras-Raf-MEK-ERK pathway.…”