The PI 3-K/Akt signaling axis is critical for both the initiation and progression of many cancers, including breast cancer, by promoting cancer cell survival and growth. Akt hyperactivation is observed in a large proportion of patients and is considered a hallmark of cancer. Much is known concerning the mechanisms that govern PI 3- K activation, and in turn Akt regulation and signaling to phenotypes associated with malignancy. This molecular information has enabled the development of PI 3-K and Akt inhibitors for cancer therapy, and many of these are in phase I and II trials. However, small molecule Akt inhibitors have shown side effects with toxicity in normal somatic cells, reflecting the fact that Akt is essential for various normal cellular functions. In contrast, uncontrolled cell division is another hallmark of human cancer, whereas most normal somatic cells are in a non-dividing, quiescent state. Consequently, certain cell cycle regulators such as Cyclin A, frequently overexpressed in cancer, are considered promising anti-cancer targets. To date, an intrinsic connection between Akt hyperactivation and aberrant cell cycle regulation has not been defined. Our preliminary studies show that Akt activity fluctuates during cell cycle and mirrors Cyclin A expression. Moreover, depletion of Cyclin A or Cdk2 dramatically reduces Akt activity, suggesting that Cdk2/Cyclin A inhibitors may specifically kill breast cancer cells with no effect of normal somatic cells.
In Aim 1, we propose that aberrant activation of Cdk2/Cyclin A in breast cancer contributes to hyperactivation of Akt. We will mechanistically define how Cdk2/Cyclin A functions as a novel upstream regulatory mechanism to promote Akt activation in a cell cycle- dependent manner. We will determine whether Cdk2 inhibitors can suppress breast cancer cell growth in vitro and in vivo.
In Aim 2, we show preliminary evidence that in a subset of triple-negative breast cancer cells, reactivation of Akt occurs subsequent to PI 3-K inhibition, and in a manner dependent on the E3 ubiquitin ligase Skp2. We will investigate the mechanistic basis for Skp2-mediated reactivation of Akt to drive phenotypes associated with malignancy in breast cancer cells. Furthermore, somatic mutations in Akt1 and Akt2 at E17K have been identified in breast cancer patients. In our preliminary studies, we show that Akt2 E17K can promote signaling and proliferation of breast epithelial cells in a growth factor and PI 3-K- independent manner, whereas Akt1 E17K cannot. We will explore the mechanistic basis for this distinction in vitro and using transgenic mice expressing Akt1 and Akt2 E17K, and examine the contribution of Skp2 in this event. Our goal in Aim 2 is to define the precise mechanisms that govern Akt activation in a PI 3-K- independent manner in breast cancer. Overall, we believe that our proposed studies will provide new molecular insights into the activation of Akt in breast tumors, that would be unresponsive to PI 3-K inhibitors. Instead, our studies will inform the use of Cdk2, Skp2 and Akt inhibitors for targeted therapy to achieve optimal treatment efficacy in the clinic.
This project focuses on elucidating the underlying molecular mechanism(s) that govern Akt activation in various types of breast cancers. We hypothesize that aberrant activation of Cdk2/Cyclin A, Skp2 and Akt somatic mutations contribute to the hyperactivation of this pathway in breast cancers. We will test our hypothesis in two specific aims using both biochemical and cellular approaches and various animal models (both xenograft and engineered transgenic mouse models). These proposed studies will provide the rationale for designing novel therapeutic approaches such as Cdk2 and/or Skp2 inhibitors to combat breast cancers by suppressing the PI3K/Akt signaling pathway.
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| Huang, Li-Yu; Zhao, Junjie; Chen, Hao et al. (2018) SCFFBW7-mediated degradation of Brg1 suppresses gastric cancer metastasis. Nat Commun 9:3569 |
| Wan, Lixin; Xu, Kexin; Wei, Yongkun et al. (2018) Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function. Mol Cell 69:279-291.e5 |
| Cheng, Ji; North, Brian J; Zhang, Tao et al. (2018) The emerging roles of protein homeostasis-governing pathways in Alzheimer's disease. Aging Cell 17:e12801 |
| Zhang, Jinfang; Bu, Xia; Wang, Haizhen et al. (2018) Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 553:91-95 |
| Shimizu, Kouhei; Nihira, Naoe Taira; Inuzuka, Hiroyuki et al. (2018) Physiological functions of FBW7 in cancer and metabolism. Cell Signal 46:15-22 |
| Zhang, Jinfang; Dang, Fabin; Ren, Junming et al. (2018) Biochemical Aspects of PD-L1 Regulation in Cancer Immunotherapy. Trends Biochem Sci 43:1014-1032 |
| Thomas, Clémence; Henry, Whitney; Cuiffo, Benjamin G et al. (2017) Pentraxin-3 is a PI3K signaling target that promotes stem cell-like traits in basal-like breast cancers. Sci Signal 10: |
| Zhang, Linli; Peng, Shan; Dai, Xiangpeng et al. (2017) Tumor suppressor SPOP ubiquitinates and degrades EglN2 to compromise growth of prostate cancer cells. Cancer Lett 390:11-20 |
| Lien, Evan C; Dibble, Christian C; Toker, Alex (2017) PI3K signaling in cancer: beyond AKT. Curr Opin Cell Biol 45:62-71 |
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