Anticancer effect of metformin on estrogen receptor-positive and tamoxifen-resistant breast cancer cell lines

Kim, Jinkyoung; Lee, Jiyun; Jang, Soon Young; Kim, Chungyeul; Choi, Yoo-Jin; Kim, Aeree

doi:10.3892/or.2016.4675

Cited by 36 publications

(29 citation statements)

References 37 publications

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“…Numerous preclinical in vivo (4,6,12,27,28) and in vitro (5,7-9,14,29) cancer models have provided evidence of metformin's anti-tumorigenic potential, which is commonly attributed to indirect whole-body effects (insulin-dependent) and/or direct (insulin-independent) effects (30). Metformin has been shown to reduce hyperinsulinemia and glycemia thereby reducing tumor cell insulin receptor (IR) expression and downstream signaling (30).…”

Section: Discussionmentioning

confidence: 99%

Metformin Accumulation Correlates with Organic Cation Transporter 2 Protein Expression and Predicts Mammary Tumor Regression In Vivo

Checkley

Rudolph

Wellberg

et al. 2017

Cancer Prevention Research

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Several epidemiological studies have associated metformin treatment with a reduction in breast cancer incidence in pre-diabetic and type II diabetic populations. Uncertainty exists regarding which patient populations and/or tumor subtypes will benefit from metformin treatment, and most preclinical in vivo studies have given little attention to the cellular pharmacology of intratumoral metformin uptake. Epidemiological reports consistently link western-style high fat diets, which drive overweight and obesity, with increased risk of breast cancer. We used a rat model of high fat diet (HFD) induced overweight and mammary carcinogenesis to define intratumoral factors that confer metformin sensitivity. Mammary tumors were initiated with N-methyl-N-nitrosourea (MNU), and rats were randomized into metformin-treated (2 mg/ml drinking water) or control groups (water only) for 8 weeks. Two-thirds of existing mammary tumors responded to metformin treatment with decreased tumor volumes (p<0.05), reduced proliferative index (p<0.01), and activated AMPK (p<0.05). Highly responsive tumors accumulated 3-fold greater metformin amounts (p<0.05) that were positively correlated with organic cation transporter-2 (OCT2) protein expression (r=0.57, P=0.038). Importantly, intratumoral metformin concentration negatively associated with tumor volume (P=0.03), and each 10 pmol increase in intratumoral metformin predicted >0.11 cm3 reduction in tumor volume. Metformin treatment also decreased proinflammatory arachidonic acid >1.5 fold in responsive tumors (P=0.023). Collectively, these preclinical data provide evidence for a direct effect of metformin in vivo and suggest that OCT2 expression may predict metformin uptake and tumor response.

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Section: Discussionmentioning

confidence: 99%

Metformin Accumulation Correlates with Organic Cation Transporter 2 Protein Expression and Predicts Mammary Tumor Regression In Vivo

Checkley

Rudolph

Wellberg

et al. 2017

Cancer Prevention Research

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“…This can be inferred from another result of Cossor et al[ 40 ], showing no significant survival benefit of metformin in post-menopausal females. Reports of the anti-cancer effect of metformin in estrogen receptor (ER)-positive breast cancer and the anti-estrogenic effect of metformin in control of abnormal endometrial proliferative disorders support this hypothesis[ 41 , 42 ]. The decrease in ER expression in tumors from females with endometrial cancer and DM treated with metformin compared to women treated with insulin also supports this hypothesis[ 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…The decrease in ER expression in tumors from females with endometrial cancer and DM treated with metformin compared to women treated with insulin also supports this hypothesis[ 42 ]. In addition, metformin repressed protein and mRNA expression of E2/ERα-regulated genes to a greater degree than tamoxifen, which resulted in inhibition of cell proliferation of ERα-positive breast cancer cells[ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Sex-dependent difference in the effect of metformin on colorectal cancer-specific mortality of diabetic colorectal cancer patients

Lee

Park

et al. 2017

WJG

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AIMTo assess factors associated with the higher effect of metformin on mortality in diabetic colorectal cancer (CRC) patients, since the factors related to the effectiveness of metformin have not been identified yet.METHODSBetween January 2000 and December 2010, 413 patients diagnosed with both stage 3/4 CRC and diabetes mellitus were identified. Patients’ demographics and clinical characteristics were analyzed. The effect of metformin on CRC-specific mortality and the interactions between metformin and each adjusted factor were evaluated.RESULTSTotal follow-up duration was median 50 mo (range: 1-218 mo). There were 85 deaths (45.9%) and 72 CRC-specific deaths (38.9%) among 185 patients who used metformin, compared to 130 total deaths (57.0%) and 107 CRC-specific deaths (46.9%) among 228 patients who did not use metformin. In multivariate analysis, survival benefit associated with metformin administration was identified (HR = 0.985, 95%CI: 0.974-0.997, P = 0.012). Interaction test between metformin and sex after adjustment for relevant factors revealed that female CRC patients taking metformin exhibited a significantly lower CRC-specific mortality rate than male CRC patients taking metformin (HR = 0.369, 95%CI: 0.155-0.881, P = 0.025). Furthermore, subgroup analysis revealed significant differences in CRC-specific mortality between the metformin and non-metformin groups in female patients (HR = 0.501, 95%CI: 0.286-0.879, P = 0.013) but not male patients (HR = 0.848, 95%CI: 0.594-1.211, P = 0.365). There were no significant interactions between metformin and other adjusted factors on CRC-specific mortality.CONCLUSIONWe showed a strong sex-dependent difference in the effect of metformin on CRC-specific mortality in advanced stage CRC patients with diabetes.

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“…Our results show a higher upregulation of pS2 when comparing with AREG and PGR. In fact, it has been reported for the ERα + MCF-7 BC cell line that, upon estrogen exposure, pS2 expression strongly increases compared to PR, not only at mRNA but also at protein levels (64,65).…”

Section: Discussionmentioning

confidence: 99%

A novel culture method that sustains ERα signaling in human breast cancer tissue microstructures

Cartaxo

Estrada

Domenici

et al. 2020

Preprint

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Background Estrogen receptor α (ERα) signaling is a defining and driving event in most breast cancers; ERα is detected in malignant epithelial cells of 75% of all breast cancers (classified as ER-positive breast cancer) and, in these cases, ERα targeting is the main therapeutic strategy. However, the biological determinants of ERα heterogeneity and the mechanisms underlying therapeutic resistance are still elusive, hampered by the challenges in developing experimental models recapitulative of intra-tumoral heterogeneity and in which ERα signaling is sustained. Ex vivo cultures of human breast cancer tissue have been proposed to retain the original tissue architecture, epithelial and stromal cell components and ERα. However, loss of cellularity, viability and ERα expression are well-known culture-related phenomena. Methods BC samples were collected and brought to the laboratory. Then they were minced, enzymatically digested, entrapped in alginate and cultured for one month. The histological architecture, cellular composition and cell proliferation of tissue microstructures were assessed by immunohistochemistry. Cell viability was assessed by measurement of cell metabolic activity. The presence of ERα was accessed by immunohistochemistry and RT-qPCR and its functionality evaluated by challenge with 17−β−estradiol and fulvestrant, respectively. Results We describe a strategy based on entrapment of breast cancer tissue microstructures in alginate capsules and their long-term culture under agitation, successfully applied to tissue obtained from 63 breast cancer patients. After one month in culture, the architectural features of the encapsulated tissue microstructures were similar to the original patient tumors: epithelial, stromal and endothelial compartments were maintained with an average of 97 of cell viability compared to day 0. In ERα-positive cases, fibers of collagen, the main extracellular matrix component in vivo , were preserved. ERα expression was retained at gene and protein levels and response to ERα stimulation and inhibition was observed at the level of downstream targets, demonstrating active ER signaling. Conclusions The proposed model system is a new methodology to study ex vivo breast cancer biology, in particular ERα signaling. It is suitable for interrogating the long-term effects of anti-endocrine drugs in a set-up that closely resembles the original tumor microenvironment, with potential application in pre- and co-clinical assays of ERα-positive breast cancer.

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Anticancer effect of metformin on estrogen receptor-positive and tamoxifen-resistant breast cancer cell lines

Cited by 36 publications

References 37 publications

Metformin Accumulation Correlates with Organic Cation Transporter 2 Protein Expression and Predicts Mammary Tumor Regression In Vivo

Metformin Accumulation Correlates with Organic Cation Transporter 2 Protein Expression and Predicts Mammary Tumor Regression In Vivo

Sex-dependent difference in the effect of metformin on colorectal cancer-specific mortality of diabetic colorectal cancer patients

A novel culture method that sustains ERα signaling in human breast cancer tissue microstructures

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