Breast cancer is amongst the most prevalent causes of death in the US. As such, despite great progress in our understanding of this disease, there still remains a dire need to explore the molecular mechanisms involved in breast tumorigenesis that will ultimately lead to new treatments and improved clinical outcomes. DNPH1 is a 2'-deoxynucleoside 5'-monophosphate N-hydrolase, whose enzymatic activity might affect nucleotide metabolism and increase levels of 2-deoxyribose that may act as an angiogenic factor. However, the precise physiological functions of DNPH1 and its mechanisms of action have remained unresolved. Notably, our published and new preliminary data demonstrate that DNPH1 is especially overexpressed in aggressive breast tumors, yet no proof of a causal relationship between DNPH1 and breast cancer formation has been established. Here, we provide in vivo evidence that DNPH1 is a promoter of tumor development: its ablation in mice impairs mammary tumor formation, angiogenesis and metastasis induced by the HER2 oncogene. Based on these and further preliminary data, we posit that DNPH1 promotes breast tumorigenesis and, accordingly, is a valid novel drug target. Specifically, we hypothesize that DNPH1 induces tumor angiogenesis and stimulates the oncogenic potential of breast cells by modulating the AMPK and Hippo/YAP1 signaling pathways. To test these hypotheses, we propose three specific aims: (i) To elucidate how DNPH1 affects cell physiology. (ii) To determine how DNPH1 stimulates angiogenesis. (iii) To decipher how DNPH1 modulates cancer cell signaling. Completion of these studies will greatly advance our mechanistic understanding of DNPH1 and its role in breast tumor development. Furthermore, our research is expected to highlight DNPH1 as a promising new drug target for breast cancer. Of note, because DNPH1 is an enzyme, small molecule drugs can be designed to inhibit its catalytic activity. Lastly, since our DNPH1 knockout mice are viable and present no obvious pathological phenotype, DNPH1 inhibitors are predicted to selectively affect cancer cells and thus display minimal side effects, a highly desirable scenario for any therapeutic drug.

Public Health Relevance

More than 40,000 patients die each year of breast cancer in the US, indicating the urgent need for innovative new avenues of therapeutic intervention. Our studies will uncover how DNPH1, an enzyme overexpressed in breast tumors, contributes to the causation of breast cancer. Such knowledge is expected to reveal novel ways to combat this disease, including by inhibiting the catalytic activity of DNPH1.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Hildesheim, Jeffrey
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University of Oklahoma Health Sciences Center
Anatomy/Cell Biology
Schools of Medicine
Oklahoma City
United States
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