Cancer growth at early stage is usually dormant and characterized with the balance between tumor cell proliferation and apoptotic death for months or years in humans. This provides ample opportunities for early cancer interventions. However, the host- cancer balance is open to environmental disturbances, i.e. constant light exposure, which can disrupt the host circadian clock gene expression and suppress pineal melatonin production. These disruptions may break the host and cancer balance and initiate the process of cancer progression. It is hypothesized that loss or diminished circadian coordination of clock gene express on within a tumor is associated with loss of circadian cell cycle coordination and accelerated tumor growth. This loss of tumor and host coordinated clock gene expression and acceleration in tumor growth induced by constant light exposure can be restored by circadian timed melatonin repletion, thereby establishing the role of melatonin in circadian dependent tumor growth control. We will conduct two series of experiments to determine the in vivo effect of circadian disruption in tumor bearing mice by constant light exposure, compared to normal light/dark conditions, upon circadian dependent rhythms in tumor growth rates, cell cycle progression and coordinated clock gene expression. We will demonstrate if daily melatonin administration in circadian disrupted tumor bearing mice under constant light exposure reverses or inhibits accelerated tumor growth and re-establishes circadian dependent cell cycle progression and coordinated clock gene expression. Although there is a growing body of evidence that constant or prolonged light exposure at night may be linked to breast cancer risk, confirmation of such findings in well-controlled animal models is necessary. The result of this proposed study will illustrate the possible connections of the circadian clock and/or clock controlled genes to genes directly controlling cellular proliferation. These clock and clock controlled genes and their products potentially represent novel targets for the control of cancer growth.
| Xie, Mingxuan; Zhu, Xiangzhu; Liu, Zhaofan et al. (2012) Membrane progesterone receptor alpha as a potential prognostic biomarker for breast cancer survival: a retrospective study. PLoS One 7:e35198 |
| Wood, Patricia A; Du-Quiton, Jovelyn; You, Shaojin et al. (2006) Circadian clock coordinates cancer cell cycle progression, thymidylate synthase, and 5-fluorouracil therapeutic index. Mol Cancer Ther 5:2023-33 |
