scholarly journals Circadian Gating of Epithelial-to-Mesenchymal Transition in Breast Cancer Cells Via Melatonin-Regulation of GSK3β

2012 ◽  
Vol 26 (11) ◽  
pp. 1808-1820 ◽  
Author(s):  
Lulu Mao ◽  
Robert T. Dauchy ◽  
David E. Blask ◽  
Lauren M. Slakey ◽  
Shulin Xiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Circadian Rhythm ◽  
Sleep Disturbances ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Glycogen Synthase ◽  
Human Breast ◽  
Light At Night ◽  
Mesenchymal Transition ◽  
Age Related

Abstract Disturbed sleep-wake cycle and circadian rhythmicity are associated with cancer, but the underlying mechanisms are unknown. Employing a tissue-isolated human breast xenograft tumor nude rat model, we observed that glycogen synthase kinase 3β (GSK3β), an enzyme critical in metabolism and cell proliferation/survival, exhibits a circadian rhythm of phosphorylation in human breast tumors. Exposure to light-at-night suppresses the nocturnal pineal melatonin synthesis, disrupting the circadian rhythm of GSK3β phosphorylation. Melatonin activates GSK3β by inhibiting the serine-threonine kinase Akt phosphorylation, inducing β-catenin degradation and inhibiting epithelial-to-mesenchymal transition, a fundamental process underlying cancer metastasis. Thus, chronic circadian disruption by light-at-night via occupational exposure or age-related sleep disturbances may contribute to cancer incidence and the metastatic spread of breast cancer by inhibiting GSK3β activity and driving epithelial-to-mesenchymal transition in breast cancer patients.

Role of E2F3 and shugoshin I in epithelial-to-mesenchymal transition and cell invasion in breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13100-e13100
Author(s):  
Shirley Jusino ◽  
Srikumar P. Chellappan ◽  
Harold I. Saavedra
Keyword(s):  
Breast Cancer ◽  
Cell Invasion ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Cellular Proliferation ◽  
Protein Localization ◽  
Breast Cancer Metastasis ◽  
Mrna Levels ◽  
Mesenchymal Transition

e13100 Background: Triple-negative breast cancer (TNBC) is the most aggressive and poorly prognostic breast cancer subtype, yet there are currently no biological therapies against this subtype. Our laboratory is finding the sources of novel biological targets in TNBC by studying the E2F transcription factors, which are essential for cellular proliferation and maintenance of genomic stability. While the deregulated Rb/E2F pathway signals the epithelial-to-mesenchymal transition (EMT), the underlining mechanism of how E2Fs drive EMT in TNBC remains unknown. We recently published that the E2F transcriptional activators (E2Fs) are overexpressed in the vast majority of TNBC and that their overexpression upregulates mitotic kinases such as TTK, which we have shown to induce EMT and invasion in TNBC cells. We also demonstrated that the E2Fs maintain genomic integrity in part through Shugoshin I (SGO1), which normally controls chromosome cohesion; however, the role of SGO1 in EMT in breast cancer is unknown. Our hypothesis is that E2F3 and SGO1 are highly expressed in TNBC and that their overexpression modulates EMT genes, thus promoting cell invasion. Methods: To test our hypothesis, we conducted siRNA transfection to knockdown E2F3 and SGO1 in MDA-MB-231 and Hs578t, which are TNBC cells. After 48 hours, we evaluated mRNA levels of EMT-related genes after E2F3 or SGO1 depletion using RT-PCR analysis. We also evaluated the effects of SGO1 depletion in protein localization by immunofluorescence. Furthermore, we evaluated the invasive behavior of MDA-MB-231 and Hs578t cells after SGO1 depletion using a Boyden Chamber Assay. Results: Our results demonstrate that E2F3 and SGO1 depletion decrease MMP3 mRNA levels. Moreover, E2F3 and SGO1 depletion restore E-cadherin expression and localization. Furthermore, E2F3 and SGO1 depletion significantly reduce cell invasion in MDA-MB-231 and Hs578t cells. Conclusions: Our results suggest that SGO1 is a promising drug target for breast cancer metastasis since EMT and invasion are essential early steps in breast cancer metastasis and E2F3 is presently undruggable.

Vitamin D regulates CXCL12/CXCR4 and epithelial-to-mesenchymal transition in a model of breast cancer metastasis to lung

Endocrinology ◽  
2021 ◽  
Author(s):  
Jiarong Li ◽  
Aimée-Lee Luco ◽  
Anne Camirand ◽  
René St-Arnaud ◽  
Richard Kremer
Keyword(s):  
Breast Cancer ◽  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Mammary Cancer ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Lung Metastases ◽  
Dietary Vitamin ◽  
Mesenchymal Transition ◽  
Primary Mammary Tumor

Abstract Vitamin D deficiency is associated with poor cancer outcome in humans, and administration of vitamin D or its analogs decreases tumor progression and metastasis in animal models. Using the mouse MMTV-PyMT model of mammary cancer, we previously demonstrated a significant acceleration of carcinogenesis in animals on a low vitamin D diet and a reduction in spontaneous lung metastases when mice received vitamin D through perfusion. We investigate here the action mechanism for vitamin D in lung metastasis in the same non-immunodeficient model and demonstrate it involves the control of epithelial to mesenchymal transition as well as interactions between chemokine CXCL12 and its receptor CXCR4. In vitro, 10 -9M vitamin D treatment modifies the phenotype of MMTV-PyMT primary mammary tumor cells and significantly decreases their invasiveness and mammosphere formation capacity by 40 and 50% respectively. Vitamin D treatment also inhibits p-STAT3, Zeb1 and vimentin by 52%, 75% and 77% respectively, and increases E-cadherin by 87%. In vivo, dietary vitamin D deficiency maintains high levels of Zeb1 and p-STAT3 in cells from primary mammary tumors, and increases CXCL12 expression in lung stroma by 64%. In lung metastases, vitamin D deficiency increases CXCL12/CXCR4 co-localization by a factor of 2.5. These findings indicate an involvement of vitamin D in mammary cancer ”seed” (primary tumor cell) and ”soil” (metastatic site), and link vitamin D deficiency to epithelial-to-mesenchymal transition (EMT), CXCL12/CXCR4 signaling and accelerated metastasis, suggesting vitamin D-repleteness in breast cancer patients could enhance the efficacy of co-administered therapies in preventing spread to distant organs.

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