Aromatase Inhibitors in Breast Cancer: Signaling Pathways Involved in Exemestane-Acquired Resistance

• Main Author: Augusto, Tiago André Sousa Vieira
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2016
• Subjects: Adenosine; Androgens; Ataxia; Autophagy; Binding sites; Biosynthesis; Breast cancer; Cardiovascular system; Cellular biology; Chromosomes; Cyclin-dependent kinases; Drugs; Endocrinology; Endometrial cancer; Enzymes; Heat shock proteins; Hormones; Kinases; Medicine; Morphology; Mutation; Nuclear physics; Oncology; Phosphorylation; Physics; Public health; Radiation therapy; Risk factors; Signal transduction; Steroids; Surgery; Therapy; Tumors; Womens health
• ISBN: 9798835558209

The use of aromatase inhibitors (AI’s) is one of the therapeutic approaches for estrogen-receptor positive (ER+ ) breast cancer, being Exemestane (Exe) the thirdgeneration steroidal AI used in clinic. Besides its therapeutic success, acquired resistance may develop causing tumor relapse. Thus, it is important to search for new strategies to surpass Exe-acquired resistance. It was already reported that autophagy may be implicated in Exe-acquired resistance. Moreover, PI3K/AKT is considered a major pathway in endocrine resistance. Therefore, using an AI-resistant breast cancer cell line (LTEDaro) it was investigated the roles of autophagy and of the PI3K/AKT survival pathway in Exe-resistance process. In that way, the effects of two different pan-PI3K inhibitors, Wortmannin (WT) and LY294002 (LY), and of one autophagic inhibitor, Spautin-1 (SP), in Exe-treated LTEDaro cells were studied. Our results demonstrate that the combination of Exemestane with LY, WT or SP induced a reduction in LTEDaro cell viability. Moreover, in Exe-treated LTEDaro cells, WT, LY and SP caused cell cycle arrest in different cell cycle phases. Furthermore, all the compounds in combination with Exe induced apoptosis through different pathways in a ROS-independent manner. LY activates apoptosis through the mitochondrial pathway, while SP caused apoptosis recruiting extrinsic pathway players. Curiously, WT induced apoptosis through the cross talk between the intrinsic and the extrinsic pathway. In addition, all the inhibitors reduced Exe-induced autophagy, as well as, the activation of the survival pathway, PI3K/AKT. Thus, by modulating the survival pathways and autophagy it may be possible to sensitize acquired-resistant breast cancer cells to Exe therapy. This work provides new insights in breast cancer therapy by elucidating the mechanisms and targets involved in Exe-acquired resistance.