Deletion of the PER3 Gene on Chromosome 1p36 in Recurrent ER-Positive Breast Cancer

University of California, Berkeley, Berkeley, California, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 08/2010; 28(23):3770-8. DOI: 10.1200/JCO.2009.27.0215
Source: PubMed


To investigate the role of the PER3 circadian rhythm gene, located within the commonly deleted region of chromosome 1p36, in human breast cancer development.
The frequency of genetic alterations at 1p36 and PER3 gene copy number status were analyzed in 180 lymph node-negative breast cancers from patients who had received treatment with chemotherapy and/or tamoxifen. The expression levels of PER3 were also analyzed using published microarray profiles from > 400 breast cancer samples. Finally, the effect of loss of Per3 on tumor susceptibility was tested using two mouse models of breast cancer.
Deletion of PER3 is directly related to tumor recurrence in patients with estrogen receptor (ER) - positive breast cancers treated with tamoxifen. Low expression of PER3 mRNA is associated with poor prognosis, particularly in a subset of tumors that are ER positive, and either luminal A or ERBB2-positive tumors. Mice deficient in Per3 showed increased susceptibility to breast cancer induced by carcinogen treatment or by overexpression of Erbb2.
Disruption of PER3 function may serve as an indicator of probability of tumor recurrence in patients with ER-positive tumors. Further investigations of this pathway may reveal links between deregulation of sleep homeostasis and breast tumorigenesis.

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Available from: Ana Bosch, Oct 05, 2015
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    • "However, no specific tumor suppressor gene at 1p36 has yet been identified. Previous studies have identified CHD5 [9] and KIF1B [10] as candidate tumor suppressor genes in this region, and more recently it was reported that disruption of PER3 function may indicate the likelihood of tumor recurrence in patients with ERα-positive tumors [11]. However, to date, no specific roles for these genes in breast cancer development have been demonstrated. "
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    ABSTRACT: Background CDK11p58, a Ser/Thr kinase that belongs to the cell division cycle 2-like 1 (CDC2L1) subfamily, is associated with cell cycle progression, tumorigenesis and apoptotic signaling. CDK11p58 is also involved in the regulation of steroid receptors, such as androgen and estrogen receptors. We previously found that CDK11p58 was abnormally expressed in prostate cancer. However, its role in breast cancer remains unclear. Methods CDK11p58 expression was evaluated by immunohistochemical staining in a tissue array. A Transwell assay was used to detect invasion and metastasis in breast cancer cells. The TaqMan® Metastasis Gene Expression Assay was used to search for potential downstream factors in the CDK11p58 signaling pathway. qRT-PCR was used to evaluate mRNA levels, and the dual luciferase array was used to analyze promoter activity. Western blotting was used to detect the protein level. Results CDK11p58 expression was negatively correlated with node status (P = 0.012), relapse status (P = 0.002) and metastasis status (P = 0.023). Kaplan-Meier survival curves indicated that the disease-free survival (DFS) was significantly poor in breast cancer patients with low CDK11 expression. Interestingly, using the breast cancer cell lines ZR-75-30 and MDA-MB-231, we found that CDK11p58 was capable of repressing the migration and invasion of ERα-positive breast cancer cells, but not ERα-negative breast cancer cells, in a kinase-dependent manner. Gene expression assays demonstrated that integrin β3 mRNA was dramatically repressed by CDK11p58, and luciferase results confirmed that the integrin β3 promoter was inhibited by CDK11p58 through ERα repression. The expression of integrin β3 was highly related to ERα signaling; ERα overexpression stimulated integrin β3 expression, whereas siRNA-mediated knockdown of ERα attenuated integrin β3 expression. Conclusions These data indicate that CDK11p58 is an anti-metastatic gene in ERα-positive breast cancer and that the regulation of integrin β3 by CDK11p58 via the repression of ERα signaling may constitute part of a signaling pathway underlying breast cancer invasion.
    BMC Cancer 08/2014; 14(1):577. DOI:10.1186/1471-2407-14-577 · 3.36 Impact Factor
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    • "Two sleep-related genes, PERIOD1 and PERIOD3, which are key regulators of our circadian rhythm, have been found to affect the apoptosis in cancer cell lines [27]. A recent study, which used a combination of human breast tumor analysis and mouse models, further showed that a deletion/reduced expression of PERIOD3 gene on chromosome 1p36 was related to the recurrence of the tumor in ER + breast cancer patients, further highlighting the role of the circadian rhythm in tumor aggressiveness [28]. "
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    ABSTRACT: Emerging evidence suggests that short sleep is associated with an increased risk of cancer; however, little has been done to study the role of sleep on tumor characteristics. In this study, we evaluated the relationship between sleep duration and tumor phenotype in 972 breast cancer patients. Sleep duration was inversely associated with tumor grade (univariate P = 0.032), particularly in postmenopausal women (univariate P = 0.018). This association did not reach statistical significance after adjustments for age, race, body mass index, hormone replacement therapy use, alcohol consumption, smoking, and physical activity in the entire study sample (P = 0.052), but it remained statistically significant (P = 0.049) among post-menopausal patients. We did not observe a statistically significant association between sleep duration and stage at diagnosis, ER, or HER2 receptor status. These results present a modest association between short duration of sleep and higher grade breast cancer in post-menopausal women. Further work needs to be done to validate these findings.
    Journal of Cancer Epidemiology 11/2013; 2013(4):467927. DOI:10.1155/2013/467927
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    • "Primer sequences for CHD5 were 5'-CTGTTGCTGCAGTTCCTTCTC-3' and 5'-ATGAAGGACAGAACCTGCCTG-3'. The RNaseP gene, which rarely has copy number changes in tumors [14], was used as an internal control for a stable diploid copy number. Primer sequences for RNaseP were 5'-CCTGGTACATGCCACTGATG-3' and 5'-AGTGTAGAGGGCAAGCCAGA-3'. "
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    ABSTRACT: The chromodomain helicase DNA binding protein 5 (CHD5) has recently been identified as a tumor suppressor in a mouse model. The CHD5 locus at 1p36 is deleted, and its mutation has been detected in breast cancer. We, therefore, evaluated whether CHD5 plays a role in human breast cancer. We screened mutations in 55 tumors, determined promoter methylation in 39 tumors, measured RNA expression in 90 tumors, analyzed protein expression in 289 tumors, and correlated expression changes with clinicopathological characteristics of breast cancer. Functional effects of CHD5 on cell proliferation, invasion and tumorigenesis were also tested. Although only one mutation was detected, CHD5 mRNA expression was significantly reduced, accompanied by frequent genomic deletion and promoter methylation, in breast cancer. The extent of methylation was significantly associated with reduced mRNA expression, and demethylating treatment restored CHD5 expression. Lower CHD5 mRNA levels correlated with lymph node metastasis (P = 0.026). CHD5 protein expression was also reduced in breast cancer, and lack of CHD5 expression significantly correlated with higher tumor stage, ER/PR-negativity, HER2 positivity, distant metastasis and worse patient survival (P ≤ 0.01). Functionally, ectopic expression of CHD5 in breast cancer cells inhibited cell proliferation and invasion in vitro and tumorigenesis in nude mice. Consistent with the inhibition of invasion, CHD5 down-regulated mesenchymal markers vimentin, N-cadherin and ZEB1 in breast cancer cells. Down-regulation of CHD5, mediated at least in part by promoter methylation, contributes to the development and progression of human breast cancer.
    Breast cancer research: BCR 05/2012; 14(3):R73. DOI:10.1186/bcr3182 · 5.49 Impact Factor
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