Susan G Komen  
I've Been Diagnosed With Breast Cancer Someone I Know Was Diagnosed Share Your Story Join Us And Stay Informed Donate To End Breast Cancer
    Home > Research & Grants > Grants Program > Research Grants > Research Grants Awarded > Abstract
    Awarded Grants
    Defining the Oncogenic Role of NPM/B23 Through Ribosome Biology

    Scientific Abstract:
    The NPM/B23 oncogene is an abundant nucleolar phosphoprotein capable of transforming numerous immortal mouse and human cell lines. However, NPM activity is not unabated in the cell; the ARF tumor suppressor inhibits NPM function through direct nucleolar interactions. NPM is thought to play a role in ribosome biogenesis, largely due to its nucleolar localization, but little has been done to verify this in light of recent findings that the nucleolus is a plurifunctional organelle. Among its ascribed properties, NPM has been shown to act as a transcription factor, p53 activator, chaperone, and shuttling protein. As a direct transcriptional target of the myc oncogene, NPM readily responds to both growth factor and hyperproliferative stimuli. Interestingly, the latter also leads to the accumulation of ARF, triggering its tumor suppressive activities. Importantly, we have found NPM overexpressed in nearly 50% of breast carcinomas that we have analyzed, implying that dysregulation of NPM may be a key event in promoting breast cancer development. In hypothesis, tumor cells that require increased protein synthesis might accumulate more NPM in an attempt to increase ribosome output. It is our goal to determine whether NPM directly regulates ribosome maturation to promote breast cancer formation and to establish the importance of ARF in deterring this effect. We propose to 1) determine the role of NPM in promoting ribosome biogenesis, 2) characterize the suppression of NPM function by ARF in breast epithelium and 2) establish a mouse model of NPM function. Using cell-based systems and new animal models, we propose to ascertain the relationship between NPM expression and breast cancer formation. The findings generated by our study could reveal an entirely new pathway, regulation of ribosome biogenesis, as a potentially novel anti-cancer target, one that might be regulated by the ARF tumor suppressor.

    Lay Abstract:
    Cancers result from an inability of a cell to control its own growth. Normally, a cell interprets external and internal signals to create a balanced growth schedule. The main interpreters of these signals within a cell are called ARF and p53, and it falls on the shoulders of these two proteins to maintain normal cell growth. In this sense, both ARF and p53 are tumor suppressors that constantly monitor the growth state of the cell. In mouse and human cancers, loss of the ARF tumor suppressor is second only to mutation of p53, providing critical evidence of ARF’s role in both monitoring and preventing the outbreak of cancer cells. A common target of ARF is the NPM/B23 oncogene, an abundant protein of the nucleolus. NPM normally responds to growth factors and, due to its nucleolar localization, is thought to transmit these growth signals to the maturing ribosome machinery. Importantly, we have found NPM overexpressed in nearly 50% of breast carcinomas that we have analyzed, implying that dysregulation of NPM may be a key event in promoting breast cancer development. In effect, tumor cells that require increased protein synthesis might accumulate more NPM in an attempt to increase ribosome output. It is our goal to determine whether NPM directly regulates ribosome maturation to promote breast cancer formation and to establish the importance of ARF in deterring this effect. Using cell-based systems and new animal models, we propose to ascertain the relationship between NPM expression and breast cancer formation. The findings generated by our study could reveal an entirely new pathway, regulation of ribosome biogenesis, as a potentially novel anti-cancer target, one that might be regulated by the ARF tumor suppressor.