A key hurdle in developing better treatments for breast cancers is a lack of understanding of the mechanisms that promote their growth, and why some breast cancers grow in response to estrogens, while others do not. Olaparib, a drug that targets PARP-1, a protein involved in many important cellular functions, was recently approved by the FDA for the treatment of breast cancers with certain types of DNA repair defects. Preliminary results suggest that Olaparib and other PARP inhibitors may also be useful for treating breast cancers that express estrogen receptor alpha (ERa) and are responsive to the hormone estrogen. In this regard, we are studying the interplay between ERa and PARP-1 in ...

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A key hurdle in developing better treatments for breast cancers is a lack of understanding of the mechanisms that promote their growth, and why some breast cancers grow in response to estrogens, while others do not. Olaparib, a drug that targets PARP-1, a protein involved in many important cellular functions, was recently approved by the FDA for the treatment of breast cancers with certain types of DNA repair defects. Preliminary results suggest that Olaparib and other PARP inhibitors may also be useful for treating breast cancers that express estrogen receptor alpha (ERa) and are responsive to the hormone estrogen. In this regard, we are studying the interplay between ERa and PARP-1 in breast cancers. We are focusing on the molecular mechanisms by which PARP-1 controls the gene-regulating activities of ERa. PARP-1 is an enzyme that chemically modifies target proteins through a process called ADP-ribosylation. We found that PARP-1 ADP-ribosylates FoxA1, a protein required for ERa function. ADP-ribosylation of FoxA1 may control the estrogen-dependent growth of breast cancer cells. In the current proposal, we will study these processes in breast cancer cells to determine the effects of PARP-1-mediated ADP-ribosylation on (1) FoxA1 activity, (2) estrogen-dependent gene expression, and (3) biological outcomes in breast cancer cells. Our proposed studies build upon a substantial amount of preliminary data and the expertise of the Kraus lab in addressing fundamental questions about PARP-1 and ERa in breast cancer cells. Collectively, our studies will explore a facet of breast cancer biology that remains largely unexplored and has great potential to change the way we diagnose and treat breast cancers. In addition, our studies will help to reveal the specific molecular endpoints of clinically relevant PARP inhibitors (e.g., Olaparib). Finally, our studies will provide new tools and approaches for studying ADP-ribosylation in cancer.

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