PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer

Abstract

Trastuzumab is the only HER2/neu-directed therapy to have received Food and Drug Administration approval for the treatment of patients with metastatic breast cancer. The efficacy of trastuzumab depends on the HER2/neu status of the tumour and the patient's prior treatment, but even when patients are selected on the basis of HER2/neu gene amplification, the single-agent response rate ranges from 12 to 30% and few patients respond to trastuzumab monotherapy. Here, we propose PTEN as a predictive biomarker for trastuzumab efficacy. Human breast cancer SKBR3 and drug-resistant SKBR3/R cells were investigated. We also examined clinical samples from patients who had been treated with trastuzumab and analysed the relationship between trastuzumab efficacy and PTEN level. The PI3K/Akt signalling pathway was observed to be highly active in the drug-resistant cells, and their level of PTEN was low. Delivery of antisense PTEN duplex siRNA significantly decreased the trastuzumab chemosensitivity of parental SKBR3 cells, and marked activation of Akt signalling pathway was also recognised. Moreover, immunohistochemical investigation revealed that trastuzumab treatment was remarkably successful in cells with elevated PTEN expression. Along with the immune-system-associated cytotoxic mechanism, several mechanisms have been proposed for the effect of trastuzumab. PTEN activity might play an important and major role in its HER2/PI3K/Akt-mediated antitumour effect, and could be a useful biomarker for predicting the efficacy of trastuzumab in the treatment of breast cancer.

Level of HER2/neu gene amplification as a predictive factor of response to trastuzumab-based therapy in patients with HER2-positive metastatic breast cancer

“…However, a number of patients with FISH-confirmed HER2-positive disease fail to respond to trastuzumab, and show primary or acquired resistance to the antibody. In vitro and in vivo findings have suggested several reasons for trastuzumab resistance, involving the phosphorylation of HER2 tyrosine kinase [12], the signaling pathways associated with the HER family of receptors [13][14][15][16], and the truncated form of HER2 protein [17]. Very recently, a role for the antibody-dependent cell-mediated cytotoxicity of natural-killer cells/monocytes has been proposed to explain the differences in response to trastuzumab-based therapy in metastatic breast cancer [18].…”

Targeting the function of the HER2 oncogene in human cancer therapeutics

“…Trastuzumab suppresses Akt signaling in some tumor cell types but not others (Normanno et al, 2002;Yakes et al, 2002;Longva et al, 2005), increases plasma phosphatase and tensin homolog (PTEN) localization and activity in cells (Nagata et al, 2004;Longva et al, 2005), and its antiproliferative and antitumor effects are attenuated by PTEN knockdown (Nagata et al, 2004;Fujita et al, 2006). Consistent with a functional role for PTEN in clinical antitumor efficacy, tumors with reduced or absent PTEN are relatively resistant to trastuzumabcontaining chemotherapy regimens (Nagata et al, 2004;Fujita et al, 2006). Although these data sets are complicated by the concomitant use of cytotoxic chemotherapy regimens, they are the only currently existing evidence linking intracellular signaling with the clinical antitumor activity of trastuzumab.…”

Targeting PTEN using small molecule inhibitors

“…Given its role as a tumour suppressor it is not surprising that PTEN has been implicated as a biomarker for certain cancers, in particular those affecting the uterus, brain, skin and prostate [12][13][14]. A complete loss of this enzyme triggers PTEN induced cellular senescence (PICS) via a p53 dependent mechanism [15].…”