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Circadian Control of Breast Cancer Development
Tumor Cell Biology I
A key aspect of breast cancer research is identifying new regulatory pathways involved in proliferation and differentiation of breast cell. Disruption of circadian rhythm has recently emerged as a new potential risk factor in the development of cancer, pointing to the core gene period 2 (per2) as a tumor suppressor. However, it remains unclear how the circadian network regulates tumor suppression, nor which, if any, of its components is either the ultimate effector that influences the fate of the cell. Our proposal is novel in its conception, approach and goals of identifying circadian-mediated mechanisms governing breast cancer initiation and progression. We propose Per2 to be a component of the checkpoint pathway and aim to investigate how signals are sensored and transduced through this protein as result of checkpoint activation. Specifically, we will investigate which pathways steps are uncoupled/altered in malignant breast cancer cells. The outcome of this research will expand the search for therapeutic targets to include core clock components. Moreover, this work will be unique in identifying circadian factors as part of the cellular surveillance mechanisms. We will then investigate how Per2 modulates the tumor suppressor activity of p53/BRCA complex by analyzing the role of Per2 in both p53-mediated induction of apoptosis and gene transcription. Results from this work will directly place Per2 as a new regulator of p53/BRCA function. Lastly, we will investigate how Per2/BRCA complex modulates the transcription of estrogen receptor alpha (ERa). The estrogen receptor is a circadian expressed protein that is present in 60% of all patients with breast cancer. We propose to investigate how Per2 exerts its regulatory function on ERa expression and to further evaluate the impact of circadian variations on its transcription. This novel research will provide mechanistic foundation for applying chronobiology to the treatment of breast cancer and will offer unprecedented molecular basis for understanding the impact that work-habits in industrialized societies have on breast cancer incidence.
Every 13 minutes a woman dies of breast cancer and, although the etiology of the disease is primarily unknown, an estimated one quarter of breast cancers cases are possibly due to heritable factors and another proportion are due to already established environmental risk factors. Interestingly, this proportion rises even more dramatically when work-habits in modern societies are under consideration suggesting that disturbance of our daily physiology, named "circadian disruption", impacts breast cancer incidence. Circadian rhythms are mechanisms that measure time on a scale of about 24 h and that adjusts our bodies to external environmental signals. Core circadian clock genes are defined as genes whose protein products are necessary components for the generation and regulation of circadian rhythms. Circadian proteins also regulate genes involved in either cell division or death; and a perturbation of the balance among these processes leads to cancer development and progression. The emerging field of chronotherapy, in which treatments for cancer and other diseases are administered at times of the day most likely to yield the greatest efficacy, will rely on deciphering the regulatory systems to which all circadian components connect, and most importantly, will depend on an understanding of the links between the circadian and cell cycle mechanisms. Today, the administration of cancer therapy based on circadian timing has shown encouraging results, but it still lacks a strong mechanistic foundation. Our research is novel in its goals to identify the pathways by which circadian components directly control cell fate. It will contribute to develop new therapeutic strategies, optimize the effectiveness of current therapies and provide explanation for the high incidence of breast cancer in modern societies.