Breast cancer is the single most common cancer in women. Although early detection followed by resection of tumors and tamoxifen treatment for estrogen receptor positive tumor patients have improved the cure frequency, the survival rate sharply declines for patients who have recurring tumors within 5 years of initial treatment. By deciphering oncogenes and tumor suppressors involved in the genesis and progression of breast cancer, better therapies can be developed that target specific molecular lesions associated with individual tumors. The objectives of this proposal are to determine roles for ING4 as a tumor suppressor in breast cancer and elucidate molecular mechanisms of ING4 function. This proposal is a direct continuation of the candidate's recently published work. The candidate identified ING4 as a gene that can suppress loss of contact inhibition in a novel tumor suppressor screen. The candidate showed that ING4 is mutated in various human cancer cell lines and is deleted in 10-20% of breast cancer cell lines as well as in primary breast tumors.
Specific aims of the proposed studies include: 1) to determine roles for ING4 as a tumor suppressor using mouse models of breast cancer and 2) to elucidate molecular mechanisms of ING4 function by identification and functional analyses of ING4 binding proteins (IBPs). The outcome of the mouse model studies will be correlated with the pathology of human breast tumors that harbor an ING4 deficiency. The mouse lines and reagents generated in the proposed studies can be directly used for the development of cancer therapy targeting the ING4 pathway. The proposed studies are to be completed in 5 years. Dr. Michael Bishop at UCSF will mentor the candidate during the first 2 years, within which time the candidate will acquire training and expertise in mouse models relevant to human breast cancer. Dr. Bishop is an ideal mentor for the candidate with his authority on the subject. The candidate will then transition into an independent academic position equivalent to an assistant professorship and continue the proposed studies to completion. The proposed studies will also provide a framework for the candidate's research program as an assistant professor to further characterize the other novel candidate tumor suppressors that she has identified in her tumor suppressor screen.
|Byron, Sara A; Min, Elizabeth; Thal, Tanya S et al. (2012) Negative regulation of NF-?B by the ING4 tumor suppressor in breast cancer. PLoS One 7:e46823|
|Tapia, Coya; Zlobec, Inti; Schneider, Sandra et al. (2011) Deletion of the inhibitor of growth 4 (ING4) tumor suppressor gene is prevalent in human epidermal growth factor 2 (HER2)-positive breast cancer. Hum Pathol 42:983-90|
|Kim, Suwon; Welm, Alana L; Bishop, J Michael (2010) A dominant mutant allele of the ING4 tumor suppressor found in human cancer cells exacerbates MYC-initiated mouse mammary tumorigenesis. Cancer Res 70:5155-62|
|Yang, Dun; Liu, Hong; Goga, Andrei et al. (2010) Therapeutic potential of a synthetic lethal interaction between the MYC proto-oncogene and inhibition of aurora-B kinase. Proc Natl Acad Sci U S A 107:13836-41|