PTEN Loss and AKT Activation in HER2-Positive Breast Carcinomas: Two Conditions not as Related as Initially Supposed

Abstract

INTRODUCTION: PI3K/AKT pathway is involved in the pathogenesis of several human cancers and is known to regulate important cellular functions, such as cell proliferation and apoptosis. AKT is activated by a variety of stimuli including those determined by growth factor receptors as HER2 in a PI3K-dependent manner. PI3K activity is opposed by the action of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) that prevents the phosphorylation and activation of AKT resulting in the inhibition of cellular proliferation, suppressing tumor formation. A loss of PTEN function also activates AKT and leads to sustained proliferative PI3K/AKT signaling. Phosphorylated AKT (pAKT) and the product of PTEN are molecules that can be assessed by immunohistochemical analysis and it is expected that they are inversely correlated. AIMS: This study was conducted to determine the pAKT and PTEN immunohistochemical expression in a series of HER2-positive primary invasive breast tumors and their association with classical clinicopathologic features (histologic and nuclear tumor grade, hormone receptors expression, lymphatic vascular invasion and proliferative activity). MATERIALS AND METHODS: We selected 104 patients with HER2-positive breast carcinoma. Representative areas of the tumors were selected for tissue microarrays (TMA) construction. We reviewed the classical morphological and immunohistochemical features and we submitted the TMA sections to the immunohistochemical stain to PTEN (28H6 clone) and pAKT (LP18 clone) (Novocastra, Newcastle, UK). Associations between the variables were made by the statistical chi-square test. RESULTS: The expression of PTEN was reduced in 20/104 (19.2%) cases and was more frequent in tumors with positive AKT (p = 0.06). The group of tumors with loss of PTEN expression showed lower proliferative activity (p=0.034). No other variable was associated to PTEN. AKT was positive in 71/104 (68.3%) cases. High grade tumors showed lower AKT positivity (46% vs. 72%) (p=0,026), however, Pakt was associated with higher Ki-67 index. CONCLUSION: Our results confirm the role of AKT in cellular proliferation, however the control mechanisms of its phosphorylation by PTEN is not the most important and others molecules, probably associated to other signaling pathways, might be involved. The inactivation of PTEN described as one of the mechanisms involved in the resistance of HER2 tumors to the trastuzumab therapy, if it exists, it might be a rare event. In our cases, reduced expression of PTEN was observed in the lower proliferative cases. On the other hand, the raising in the cellular proliferation was associated with diffuse expression of PTEN, probably reflex of its activation to control cell proliferation.