Abstract 1881: Insulin receptor targeting in breast cancer through yeast surface display
| Autor: | Jie Ying Chan, Kelly LaPara, Benjamin Hackel, Douglas Yee |
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| Rok vydání: | 2016 |
| Předmět: | |
| Zdroj: | Cancer Research. 76:1881-1881 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Selective estrogen receptor modulators (SERMs) such as tamoxifen are used to treat estrogen receptor (ER) positive breast cancers, the most common intrinsic subtype. The development of secondary resistance to SERMs is an unsolved clinical dilemma, leading to the exploration, and approval, of therapies targeting growth factor signaling pathways. The insulin-like growth factor (IGF) system is well documented to cooperate with ER and is implicated as a contributor to endocrine resistance. Unfortunately, antibodies directed against Type I IGF receptor (IGF1R) failed to demonstrate clinical efficacy in endocrine resistant breast cancer. We developed a tamoxifen resistant (TamR) model to further identify the role for this system in endocrine resistance. In these cells, IGF1R levels are low but the level of insulin receptor (InsR), a closely related receptor of IGF1R still remains functional. Thus, we hypothesize that InsR may serve as a compensatory pathway to the loss of IGF1R in TamR cells and InsR may be a target in the therapy of endocrine resistant breast cancer. Indeed, our results showed that TamR breast cancer cells are more sensitive to insulin stimulation than wild-type cells. As compared to the parental cells, insulin-stimulated TamR cells showed enhanced PI3K/AKT and MAPK/ERK activation, greater monolayer and anchorage-independent growth. Suppression of InsR expression with either lentiviral shRNA or pharmacological methods in TamR cells was able to attenuate their sensitivity towards insulin-regulated PI3K/MAPK activation and growth, suggesting InsR targeting may be necessary. To target InsR, we are developing InsR-selective small protein scaffolds - the 10th type III domain of human fibronectin (Fn3) and T7 phage gene 2 protein (Gp2) using yeast surface display. This technique has arisen as an alternative candidate to bind cells surface proteins. Compared to antibodies, protein scaffolds are smaller ( Citation Format: Jie Ying Chan, Kelly LaPara, Benjamin Hackel, Douglas Yee. Insulin receptor targeting in breast cancer through yeast surface display. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1881. |
| Databáze: | OpenAIRE |
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