Role of STAT3 Phosphorylation in Ethanol-Mediated Proliferation of Breast Cancer Cells

Narayanan, Poornima devi; Nandabalan, Sangeetha Kadapakkam; Baddireddi, Lakshmi Subhadra

doi:10.4048/jbc.2016.19.2.122

Cited by 17 publications

(15 citation statements)

References 25 publications

(24 reference statements)

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“…More importantly, after chronic exposure to alcohol, less aggressive breast cancer cells are transformed into a more aggressive phenotype which is demonstrated by the scattering spheroids in the 3-D culture system [32, 33]. In some studies, alcohol is shown to promote the growth of breast cancer cells both in vitro and in vivo [21–23, 43–45]. Alcohol-induced increase in the growth of breast cancer cells may result from either enhanced cell proliferation or promotion of survival.…”

Section: Alcohol-induced Aggressiveness Of Breast Cancermentioning

confidence: 99%

Cellular and molecular mechanisms underlying alcohol-induced aggressiveness of breast cancer

Wang

Zhang

et al. 2017

Pharmacological Research

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Breast cancer is a leading cause of morbidity and mortality in women. Both Epidemiological and experimental studies indicate a positive correlation between alcohol consumption and the risk of breast cancer. While alcohol exposure may promote the carcinogenesis or onset of breast cancer, it may as well enhance the progression and aggressiveness of existing mammary tumors. Recent progress in this line of research suggests that alcohol exposure is associated with invasive breast cancer and promotes the growth and metastasis of mammary tumors. There are multiple potential mechanisms involved in alcohol-stimulated progression and aggressiveness of breast cancer. Alcohol may increase the mobility of cancer cells by inducing cytoskeleton reorganization and enhancing the cancer cell invasion by causing degradation and reconstruction of the extracellular matrix (ECM). Moreover, alcohol may promote the epithelial-mesenchymal transition (EMT), a hallmark of malignancy, and impair endothelial integrity, thereby increasing the dissemination of breast cancer cells and facilitating metastasis. Furthermore, alcohol may stimulate tumor angiogenesis through the activation of cytokines and chemokines which promotes tumor growth. Additionally, alcohol may increase the cancer stem cell population which affects neoplastic cell behavior, aggressiveness, and the therapeutic response. Alcohol can be metabolized in the mammary tissues and breast cancer cells which produces reactive oxygen species (ROS), causing oxidative stress. Recent studies suggest that the epidermal growth factor receptor (EGFR) family, particularly ErbB2 (a member of this family), is involved in alcohol-mediated tumor promotion. Breast cancer cells or mammary epithelial cells over-expressing ErbB2 are more sensitive to alcohol’s tumor promoting effects. There is considerable cross-talk between oxidative stress and EGFR/ErbB2 signaling. This review further discusses how the interaction between oxidative stress and EGFR/ErbB2 signaling contributes to the cellular and molecular events associated with breast cancer aggressiveness. We also discuss the potential therapeutic approaches for cancer patients who drink alcoholic beverages.

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Section: Alcohol-induced Aggressiveness Of Breast Cancermentioning

confidence: 99%

Cellular and molecular mechanisms underlying alcohol-induced aggressiveness of breast cancer

Wang

Zhang

et al. 2017

Pharmacological Research

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“…These results show that Co-exo stimulated breast cancer cells through cytokines, such as IL-6, to modify their proliferative and metastatic properties. According to the literature 31, STAT3 is the main transcription factor through which IL-6 signals in target cells, where it regulates many downstream target genes including those that regulate cell cycle and proliferation (e.g., CyclinD1) 32 and tumor metastasis (e.g., MMP2 and MMP9) 33. Therefore, we next examined the cell cycle, clone formation and metastasis ability, and the expression of their corresponding genes, in MCF-7 cells exposed to Co-exo and Mac-exo exosomes, and control cells.…”

Section: Resultsmentioning

confidence: 99%

Exosomes from Macrophages Exposed to Apoptotic Breast Cancer Cells Promote Breast Cancer Proliferation and Metastasis

Yu¹,

Zhang²,

Zhang³

et al. 2019

J. Cancer

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Exosomes have recently become the subject of increasing research interest. Interactions between tumor and host cells via exosomes play crucial roles in the initiation, progression and invasiveness of breast cancer. In our study, we used exosomes isolated from a co-culture model of THP-1-derived macrophages exposed to apoptotic MCF-7 or MDA-MB-231 breast cancer cell line cells to investigate their effects on naïve MCF-7 or MDA-MB-231 cells in vitro and in vivo. This post-chemotherapy tumor microenvironment model allowed us to explore possible mechanisms that explain increased proliferation and metastasis of breast cancer seen in some patients. Our results suggest that while exosomes derived from macrophages normally inhibit proliferation and metastasis of MCF-7 or MDA-MB-231 cells, exposure of macrophages to breast cancer cells that have experienced chemotherapy are modified them to promote these processes. Exosomes from macrophages exposed to apoptotic cancer cells have increased amounts of IL-6 that increases the phosphorylation of STAT3, which likely explains the increased transcription of STAT3 target genes such as CyclinD1, MMP2 and MMP9. These observations suggest that the inhibition of exosome secretion and STAT3 signaling pathway activation might suppress the growth and metastasis of malignant tumors, and provide new targets for therapeutic treatment of malignant tumors after chemotherapy.

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“…The MCF-7 breast cancer cell line harbors endogenous wild-type p53 expression and is often used as a cellular model for detecting alcohol-induced carcinogenesis [35–37]. We demonstrated that alcohol exposure triggers a p53-dependent signaling cascade and cell cycle arrest, while p53 knockdown influenced alcohol-induced activities as indicated by attenuated cell cycle arrest and intensified DNA damage.…”

Section: Introductionmentioning

confidence: 85%

p53 pathway determines the cellular response to alcohol-induced DNA damage in MCF-7 breast cancer cells

et al. 2017

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Alcohol consumption is associated with increased breast cancer risk; however, the underlying mechanisms that contribute to mammary tumor initiation and progression are unclear. Alcohol is known to induce oxidative stress and DNA damage; likewise, p53 is a critical modulator of the DNA repair pathway and ensures genomic integrity. p53 mutations are frequently detected in breast and other tumors. The impact of alcohol on p53 is recognized, yet the role of p53 in alcohol-induced mammary carcinogenesis remains poorly defined. In our study, we measured alcohol-mediated oxidative DNA damage in MCF-7 cells using 8-OHdG and p-H2AX foci formation assays. p53 activity and target gene expression after alcohol exposure were determined using p53 luciferase reporter assay, qPCR, and Western blotting. A mechanistic study delineating the role of p53 in DNA damage response and cell cycle arrest was based on isogenic MCF-7 cells stably transfected with control (MCF-7/Con) or p53-targeting siRNA (MCF-7/sip53), and MCF-7 cells that were pretreated with Nutlin-3 (Mdm2 inhibitor) to stabilize p53. Alcohol treatment resulted in significant DNA damage in MCF-7 cells, as indicated by increased levels of 8-OHdG and p-H2AX foci number. A p53-dependent signaling cascade was stimulated by alcohol-induced DNA damage. Moderate to high concentrations of alcohol (0.1–0.8% v/v) induced p53 activation, as indicated by increased p53 phosphorylation, reporter gene activity, and p21/Bax gene expression, which led to G0/G1 cell cycle arrest. Importantly, compared to MCF-7/Con cells, alcohol-induced DNA damage was significantly enhanced, while alcohol-induced p21/Bax expression and cell cycle arrest were attenuated in MCF-7/sip53 cells. In contrast, inhibition of p53 degradation via Nutlin-3 reinforced G0/G1 cell cycle arrest in MCF-7 control cells. Our study suggests that functional p53 plays a critical role in cellular responses to alcohol-induced DNA damage, which protects the cells from DNA damage associated with breast cancer risk.

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Role of STAT3 Phosphorylation in Ethanol-Mediated Proliferation of Breast Cancer Cells

Cited by 17 publications

References 25 publications

Cellular and molecular mechanisms underlying alcohol-induced aggressiveness of breast cancer

Cellular and molecular mechanisms underlying alcohol-induced aggressiveness of breast cancer

Exosomes from Macrophages Exposed to Apoptotic Breast Cancer Cells Promote Breast Cancer Proliferation and Metastasis

p53 pathway determines the cellular response to alcohol-induced DNA damage in MCF-7 breast cancer cells

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