Abstract LB-A21: PRAS40 (AKT1S1) ablation modulates breast cancer by increasing tumor-free survival in HER-2/neu overexpressing mice

Abstract

Abstract HER-2 is over-expressed in around 20% of breast cancer patients and is correlated with a shorter relapse time and poor prognosis. This makes it crucial to identify novel downstream molecular targets in spite of a number of clinically approved drugs that target HER-2. In this study, we determined if loss of proline-rich Akt substrate of 40 kDa (PRAS40) gene increases tumor-free survival in HER-2/neu over-expressing double transgenic mice. Tumor kinetics was determined in HER-2 overexpressing PRAS40+/+ (wild-type) versus PRAS40-/- (knock-out) mice. Mammary intraepithelial neoplasias (MINs or precancerous lesions) in mammary tissues were analyzed using whole mount analysis. We observed significant increase of tumor-free survival in HER-2 overexpressing PRAS40-/- versus PRAS40+/+ parous female mice, however this effect was not significant in virgin mice. In virgin mice, we observed post-menopausal switch of tumor-free survival. The pre-menopausal protection from mammary tumors could be due to presence of Estrogen (ER). Irrespective of parity, we observed significant reduction of mammary intraepithelial neoplasias (MINs or precancerous lesions) in PRAS40-/- versus PRAS40+/+ mice. To investigate the mechanism of action of ER in HER-2 over-expressing mice we treated ER positive cells with Doxorubicin, ER or the combination in vitro. Modulation of cell proliferation and apoptosis was determined by PRAS40 transient knockdown (siPRAS40) versus non-targeting (NT) following treatment in ER positive ZR-751 cells. To interrogate the effect of Doxorubicin, ER, in vitro, cell lines were treated with 6-24 hr Doxorubicin, ER or both. Doxorubicin, ER or combination treatment led to significant reduction in proliferation and increased apoptosis in siPRAS40 versus non-targeting (NT) ZR-751 cells. Together, our data suggests that ER may have an effect upon PRAS40 knockdown in vitro and in vivo. Our results show that PRAS40 could be a novel ‘druggable’ target for treating aggressive HER-2 positive breast cancers. Citation Format: Ritu Malla, Jesika S. Faridi. PRAS40 (AKT1S1) ablation modulates breast cancer by increasing tumor-free survival in HER-2/neu overexpressing mice [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A21.