Identifying chemopreventive agents for obesity-associated cancers using an efficient, 3D high-throughput transformation assay

Benham, Vanessa; Bullard, Blair; Dexheimer, Thomas S.; Bernard, Matthew P.; Neubig, Richard R.; Liby, Karen T.; Bernard, Jamie J.

doi:10.1038/s41598-019-46531-y

Cited by 5 publications

(3 citation statements)

References 47 publications

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“…Considering MCF10A as a representative of normal breast epithelial cells, it could be assumed that SVA had a small protective function. This could be attributed to the fact that at a concentration of 2.5 μM SVA, MCF10A cannot undergo a FGF2-driven malignant transformation in 3D cell cultures (led by using ultra-low attachment plates) [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Simvastatin treatment varies the radiation response of human breast cells in 2D or 3D culture

et al. 2020

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SummaryBackground Statins inhibit the cholesterol biosynthesis and are used as cholesterol-lowering agents in fat-metabolism disorders. Furthermore, several studies state that statins have supportive functions in breast cancer treatment. Therefore, simvastatin (SVA) as a potential radiosensitizer should be investigated on the basis of human breast cells. Methods First, an optimal concentration of SVA for normal (MCF10A) and cancer (MCF-7) cells was identified via growth and cytotoxicity assays that, according to the definition of a radiosensitizer in the narrower sense, enhances the effect of radiation therapy but has no cytotoxic effect. Next, in combination with radiation SVA’s influence on DNA repair capacity and clonogenic survival in 2D and 3D was determined. Furthermore cell cycle distribution, expression of survivin and connective tissue growth factor (CTGF) as well as ERK1 map kinase were analysed. Results 1 μM SVA was identified as highest concentration without an influence on cell growth and cytotoxicity and was used for further analyses. In terms of early and residual γH2AX-foci, SVA affected the number of foci in both cell lines with or without irradiation. Different radiation responses were detected in 2D and 3D culture conditions. During the 2D cultivation, a radiosensitizing effect within the clonogenic survival was observable, but not in 3D. Conclusion The present study suggests that SVA may have potential for radiosensitization. Therefore, it is important to further investigate the role of SVA in relation to the extent of radiosensitization and how it could be used to positively influence the therapy of breast cancer or other entities.

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Section: Discussionmentioning

confidence: 99%

Simvastatin treatment varies the radiation response of human breast cells in 2D or 3D culture

et al. 2020

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“…The fibroblast growth factor receptor-1 (FGFR1) inhibitor, PD166866, was purchased from SelleckChem, growth factors were purchased from R&D Systems (insulin-like growth factor-1 (IGF1) and FGF2) and estradiol was purchased from Sigma-Aldrich. The PD166866 concentration used herein was based upon our previously published dose-response studies showing that 2.5 µM blocks FGF2-stimulated malignant transformation in JB6 P + cells [11].…”

Section: Methodsmentioning

confidence: 99%

The Use of Human Serum Samples to Study Malignant Transformation: A Pilot Study

Holowatyj

Gigic

Warby

et al. 2021

Cells

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Obesity and excess adiposity account for approximately 20% of all cancer cases; however, biomarkers of risk remain to be elucidated. While fibroblast growth factor-2 (FGF2) is emerging as an attractive candidate biomarker for visceral adipose tissue mass, the role of circulating FGF2 in malignant transformation remains unknown. Moreover, functional assays for biomarker discovery are limited. We sought to determine if human serum could stimulate the 3D growth of a non-tumorigenic cell line. This type of anchorage-independent 3D growth in soft agar is a surrogate marker for acquired tumorigenicity of cell lines. We found that human serum from cancer-free men and women has the potential to stimulate growth in soft agar of non-tumorigenic epithelial JB6 P+ cells. We examined circulating levels of FGF2 in humans in malignant transformation in vitro in a pilot study of n = 33 men and women. Serum FGF2 levels were not associated with colony formation in epithelial cells (r = 0.05, p = 0.80); however, a fibroblast growth factor receptor-1 (FGFR1) selective inhibitor significantly blocked serum-stimulated transformation, suggesting that FGF2 activation of FGFR1 may be necessary, but not sufficient for the transforming effects of human serum. This pilot study indicates that the FGF2/FGFR1 axis plays a role in JB6 P+ malignant transformation and describes an assay to determine critical serum factors that have the potential to promote tumorigenesis.

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“…109,110 Statins block the malignant transformation of human MCF10A breast cells by factors released from VAT. 111 These studies suggest the potential for adipocyte-derived lipids and obesity-associated metabolites to exert a negative impact on breast cancer risk and prognosis.…”

Section: Lipid Mediators and Metabolitesmentioning

confidence: 98%

The Tumor Promotional Role of Adipocytes in the Breast Cancer Microenvironment and Macroenvironment

Bernard

Wellberg

2021

The American Journal of Pathology

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The role of the adipocyte in the tumor microenvironment has received significant attention as a critical mediator of the obesity-cancer relationship. Current estimates indicate that 650 million adults have obesity, and thirteen cancers, including breast cancer, are estimated to be associated with obesity. Even in people with a normal body mass index, adipocytes are key players in breast cancer progression because of the proximity of tumors to mammary adipose tissue. Outside the breast microenvironment, adipocytes influence metabolic and immune function and produce numerous signaling molecules, all of which affect breast cancer development and progression. The current epidemiologic data linking obesity, and importantly adipose tissue, to breast cancer risk and prognosis, focusing on metabolic health, weight gain, and adipose distribution as underlying drivers of obesity-associated breast cancer is presented here. Bioactive factors produced by adipocytes, both normal and cancer associated, such as cytokines, growth factors, and metabolites, and the potential mechanisms through which adipocytes influence different breast cancer subtypes are highlighted.

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Identifying chemopreventive agents for obesity-associated cancers using an efficient, 3D high-throughput transformation assay

Cited by 5 publications

References 47 publications

Simvastatin treatment varies the radiation response of human breast cells in 2D or 3D culture

Simvastatin treatment varies the radiation response of human breast cells in 2D or 3D culture

The Use of Human Serum Samples to Study Malignant Transformation: A Pilot Study

The Tumor Promotional Role of Adipocytes in the Breast Cancer Microenvironment and Macroenvironment

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