Abstract Hypoxia is one of the key microenvironmental factors that impinges upon tumor progression and metastasis of solid tumors such as breast cancer. While evaluating the impact of hypoxia, our group made an unanticipated but striking observation that in chronic hypoxia, mammary tumors display a remarkable increase in the number of nucleoli per cell. We found that this increase is concomitant with upregulated activity of the nucleolus. In the nucleolus, RNA Pol I transcribes rDNA (contains the sequences of 18S, 5.8S and 28S rRNAs) to drive ribosome biogenesis. We contend that this increased ribosome biogenesis is essential for hypoxic cell survival and subsequent disease progression. In response to hypoxia, nucleolar ERK signaling activity is increased. Increased ERK directly impinges upon the activity of UBF, a nucleolus-specific transcription activator, which activates RNA Pol I. We contend that this increased nucleolar activity is a vulnerability of hypoxic tumor cells. Our objective is to test an approach to exploit the dependence of hypoxic breast cancer cells on ERK activation. We contend that debilitating the rRNA biogenesis following nucleolar ERK activation following hypoxic stress will remarkably restrict the tumor growth and metastatic spread of breast cancer cells. To test this, we will adopt carefully designed cellular and animal experimental approaches to test the effect of antagonizing ERK and RNA Pol I activity on metastatic progression. Additionally, we will identify mechanistic details of nucleolar ERK functions. Overall, our work will reveal novel aspects of nucleolar ERK response of tumor cells that support their survival and metastatic ability under hypoxia.