Abstract
Growing genetic and epidemiological evidence suggests a direct connection between the disruption of circadian rhythm and breast cancer. Moreover, the expression of several molecular components constituting the circadian clock machinery has been found to be modulated by estrogen-estrogen receptor α (E2-ERα) signaling in ERα-positive breast cancer cells. In this study, we investigated the regulation of CLOCK expression by ERα and its roles in cell proliferation. Immunohistochemical analysis of human breast tumor samples revealed high expression of CLOCK in ERα-positive breast tumor samples. Subsequent experiments using ERα-positive human breast cancer cell lines showed that both protein and mRNA levels of CLOCK were up-regulated by E2 and ERα. In these cells, E2 promoted the binding of ERα to the EREs (estrogen-response elements) of CLOCK promoter, thereby up-regulating the transcription of CLOCK. Knockdown of CLOCK attenuated cell proliferation in ERα-positive breast cancer cells. Taken together, these results demonstrated that CLOCK could be an important gene that mediates cell proliferation in breast cancer cells.
Highlights
IntroductionProlonged exposure to estrogen is thought to be a major factor contributing to the development and progression of breast cancer [1,2]
Breast cancer is one of the most prevalent causes of cancer death among women
CLOCK protein is upregulated in ERa-positive breast tumor
Summary
Prolonged exposure to estrogen is thought to be a major factor contributing to the development and progression of breast cancer [1,2]. The molecular mechanism of breast cancer induced by estrogen is thought to occur through the binding of estrogen to the transcription factor estrogen receptors (ERs), which binds to estrogen response elements (EREs) in the promoters or regulatory regions of target genes. ERb is expressed in breast cancer, but its role is still elusive [6]. ERa can bind to the promoter or regulatory regions of target genes that contain imperfect or truncated EREs, and activate their transcription [7,8]. E2 promotes the proliferation of breast cancer cells through a number of established pathways [3]
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