The nuclear-factor ?B (NF-?B) family of transcription factors plays a central role in regulating many physiological processes including innate and adaptive immunity. In addition, accumulating evidence suggests that inappropriate activation of NF-?B occurs in many types of human cancers. Although genetic alterations of specific core components of the NF-?B signaling pathway have been identified in a few lymphoid malignancies, the molecular alterations that lead to and the consequences of increased NF-:B activity in the pathogenesis of human cancers remain incompletely understood. In recent work, we have identified the inhibitor of ?B kinase 5 (IKBKE, IKKi IKK5) as amplified and overexpressed in a substantial subset of human breast cancer cell lines and tumors. IKK5 is required for the survival of breast cancer cell lines that harbor IKK5 copy number gain and confers a tumorigenic phenotype when expressed in immortalized human mammary epithelial cells. Breast cancer cell lines and tumors that overexpress IKK5 exhibit increased NF-?B activity, which is essential for their transformed phenotype. These observations classify IKK5 as a breast cancer oncogene and may also explain the increased NF-?B activity previously described in a subset of human breast cancers. Based on these observations, this proposal focuses on investigating the role of IKK5 in breast cancer pathogenesis. Specifically, biochemical, genetic and molecular biological approaches will be applied to identify and characterize which substrates and interacting proteins of this non-canonical IKK are critical for tumorigenicity, to investigate how ubiquitination regulates IKK5 activity and function in breast cancer and to dissect the roles of IKK5 in tumor initiation and maintenance in genetically engineered mice. Investigating the regulation and function of IKK5 in breast cancer development will not only enhance our mechanistic understanding of this non-canonical IKK regulator but will also clarify the role of NF-?B signaling in the development of human epithelial cancers. In addition, these studies will provide a foundation for strategies to target this kinase oncogene therapeutically.
Although significant progress has been made in the diagnosis and treatment of breast cancer, we lack curative targeted therapies for many advanced stage breast cancers. This proposal focuses on deciphering the role of a newly discovered oncogene in breast cancer initiation and maintenance. These biochemical, cell and animal-based studies will not only provide insight into the biology of this kinase oncogene but will serve as a foundation for translational studies for the development of novel therapeutic agents.
|Horn, Heiko; Lawrence, Michael S; Chouinard, Candace R et al. (2018) NetSig: network-based discovery from cancer genomes. Nat Methods 15:61-66|
|Li, Ji; Choi, Peter S; Chaffer, Christine L et al. (2018) An alternative splicing switch in FLNB promotes the mesenchymal cell state in human breast cancer. Elife 7:|
|Aguirre, Andrew J; Hahn, William C (2018) Synthetic Lethal Vulnerabilities in KRAS-Mutant Cancers. Cold Spring Harb Perspect Med 8:|
|Zwang, Yaara; Jonas, Oliver; Chen, Casandra et al. (2017) Synergistic interactions with PI3K inhibition that induce apoptosis. Elife 6:|
|Kim, Jong Wook; Abudayyeh, Omar O; Yeerna, Huwate et al. (2017) Decomposing Oncogenic Transcriptional Signatures to Generate Maps of Divergent Cellular States. Cell Syst 5:105-118.e9|
|Wang, Belinda; Krall, Elsa Beyer; Aguirre, Andrew James et al. (2017) ATXN1L, CIC, and ETS Transcription Factors Modulate Sensitivity to MAPK Pathway Inhibition. Cell Rep 18:1543-1557|
|Meyers, Robin M; Bryan, Jordan G; McFarland, James M et al. (2017) Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. Nat Genet 49:1779-1784|
|Krall, Elsa B; Wang, Belinda; Munoz, Diana M et al. (2017) KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. Elife 6:|
|Choudhury, Atish D; Schinzel, Anna C; Cotter, Maura B et al. (2017) Castration Resistance in Prostate Cancer Is Mediated by the Kinase NEK6. Cancer Res 77:753-765|
|Tsherniak, Aviad; Vazquez, Francisca; Montgomery, Phil G et al. (2017) Defining a Cancer Dependency Map. Cell 170:564-576.e16|
Showing the most recent 10 out of 27 publications