Nanette Bishopric, M.D.
Professor of Medicine
Description of Research
EP300 and its substrates as growth regulators in breast cancer. Dr. Bishopric's laboratory is focused on understanding the role of acetyltransferase EP300 (p300, KAT3B) in the control of cell growth. In addition to playing critical roles in driving proliferation and differentiation, our laboratory has shown that EP300 is a critical part of the response to stress in a number of terminally differentiated cell types, in part by regulating cell survival and DNA damage response pathways. EP300 is a transcriptional activator that works by acetylating lysine residues on transcription factors, histones and other substrates; this modification favors an open chromatin configuration and assembly of a functional polymerase II complex.
In mammals, EP300 has a paralogue, CREB-binding protein (CBP, KAT3A), with extensive sequence homology as well as highly similar roles in fundamental cell processes. These 2 genes likely represent a duplication of a single ancestral gene during mammalian evolution. The proteins have been thought to be functionally identical and thus are frequently mentioned in tandem (e.g., “EP300/CBP”). Nonetheless, genetic data suggest that these 2 proteins have acquired different, non-overlapping functions, including specific gene and microRNA targets. In particular, Dr. Bishopric’s laboratory has produced strong evidence that these two proteins play opposite roles in the regulation of pathological cardiac growth. To elucidate the distinct properties of CBP and EP300, we have performed genome-wide transcriptional analysis in animals deficient for one or the other gene, and are investigating the small number of genes that require only EP300 or CBP under conditions of stress.
Dr. Bishopric’s lab is presently investigating the role of EP300 in the growth of estrogen receptor-positive breast cancer. It remains highly controversial whether p300 functions as a tumor promoter or suppressor. Both small studies and large-scale cancer genome sequencing efforts have revealed that loss of EP300 is extremely common in breast cancer, with reduced transcript levels due to copy number loss or other unidentified mechanisms. This pattern is not observed with CBP, suggesting that EP300 has a unique role in breast cancer promotion. Consistent with this, investigators in the Bishopric laboratory have demonstrated that engineered EP300 loss in MCF-7 cells confers accelerated growth in vitro and increased tumorigenic potential in xenograft models. The mechanism may be through loss of EP300-dependent tumor suppressors, including microRNA miR-let-7c, which has been shown to inhibit breast cell proliferation and promote mammary differentiation. Ongoing work will establish whether p300 regulates miR-let7c directly or indirectly; whether manipulation of p300 HAT activity by specific small molecule agonists and antagonists can alter the tumorigenicity or aggressiveness of breast cancer; and whether the effects of p300 are estrogen- or ER-dependent.
Related projects in the laboratory focus on understanding the link between the anti-tumor effects of breast cancer chemotherapeutics and their effects on heart cell survival. Some breast ancer treatments are highly toxic to the myocardium, e.g. the anthracycline doxorubicin; newer agents, including HDAC inhibitors may be cardioprotective by transiently enhancing EP300 levels. Insights from this work may lead to improved methods for protecting the heart and maximizing the effectiveness of available breast cancer treatments.
- Identified EP300, a cellular target of adenovirus E1A oncoprotein, as a nodal, quantitative regulator of cardiac myocyte growth. p300 is a nuclear acetyltransferase that promotes transcription in a gene-specific manner by modifying histones and certain transcription factors.
- Investigating the role of p300 in the growth of estrogen receptor-positive breast cancer, the collective findings of Dr. Bishopric’s lab indicate that p300 acts as a tumor suppressor in ER+ breast cancer in part by controlling levels of anti-oncogenic microRNAs.
Selected Cancer-Related Publications
Collaborating in the Multidisciplinary Research Program(s):