scholarly journals Investigating New Therapeutic Strategies Targeting Hyperinsulinemia's Mitogenic Effects in a Female Mouse Breast Cancer Model

Endocrinology ◽  
2013 ◽  
Vol 154 (5) ◽  
pp. 1701-1710 ◽  
Author(s):  
Ran Rostoker ◽  
Keren Bitton-Worms ◽  
Avishay Caspi ◽  
Zila Shen-Orr ◽  
Derek LeRoith
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Breast Tumor ◽  
Experimental Studies ◽  
Tumor Development ◽  
Treated Group ◽  
Tumor Growth Rate ◽  
Breast Cancer Patients ◽  
Mitogenic Effect

Abstract Epidemiological and experimental studies have identified hyperinsulinemia as an important risk factor for breast cancer induction and for the poor prognosis in breast cancer patients with obesity and type 2 diabetes. Recently it was demonstrated that both the insulin receptor (IR) and the IGF-IR mediate hyperinsulinemia's mitogenic effect in several breast cancer models. Although IGF-IR has been intensively investigated, and anti-IGF-IR therapies are now in advanced clinical trials, the role of the IR in mediating hyperinsulinemia's mitogenic effect remains to be clarified. Here we aimed to explore the potential of IR inhibition compared to dual IR/IGF-IR blockade on breast tumor growth. To initiate breast tumors, we inoculated the mammary carcinoma Mvt-1 cell line into the inguinal mammary fat pad of the hyperinsulinemic MKR female mice, and to study the role of IR, we treated the mice bearing tumors with the recently reported high-affinity IR antagonist-S961, in addition to the well-documented IGF-IR inhibitor picropodophyllin (PPP). Although reducing IR activation, with resultant severe hyperglycemia and hyperinsulinemia, S961-treated mice had significantly larger tumors compared to the vehicle-treated group. This effect maybe secondary to the severe hyperinsulinemia mediated via the IGF-1 receptor. In contrast, PPP by partially inhibiting both IR and IGF-IR activity reduced tumor growth rate with only mild metabolic consequences. We conclude that targeting (even partially) both IR and IGF-IRs impairs hyperinsulinemia's effects in breast tumor development while simultaneously sparing the metabolic abnormalities observed when targeting IR alone with virtual complete inhibition.

scholarly journals TFEB is a master regulator of tumor-associated macrophages in breast cancer

2020 ◽  
Vol 8 (1) ◽  
pp. e000543 ◽  
Author(s):  
Yong Li ◽  
Johnie Hodge ◽  
Qing Liu ◽  
Junfeng Wang ◽  
Yuzhen Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Tumor Growth ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Breast Tumor ◽  
Tumor Development ◽  
Tumor Associated Macrophages ◽  
And Function ◽  
The Impact

BackgroundTumor-associated macrophages (TAMs) play key roles in the development of many malignant solid tumors including breast cancer. They are educated in the tumor microenvironment (TME) to promote tumor growth, metastasis, and therapy resistance. However, the phenotype of TAMs is elusive and how to regulate them for therapeutic purpose remains unclear; therefore, TAM-targeting therapies have not yet achieved clinical success. The purposes of this study were to examine the role of transcription factor EB (TFEB) in regulating TAM gene expression and function and to determine if TFEB activation can halt breast tumor development.MethodsMicroarrays were used to analyze the gene expression profile of macrophages (MΦs) in the context of breast cancer and to examine the impact of TFEB overexpression. Cell culture studies were performed to define the mechanisms by which TFEB affects MΦ gene expression and function. Mouse studies were carried out to investigate the impact of MΦ TFEB deficiency or activation on breast tumor growth. Human cancer genome data were analyzed to reveal the prognostic value of TFEB and its regulated genes.ResultsTAM-mimic MΦs display a unique gene expression profile, including significant reduction in TFEB expression. TFEB overexpression favorably modulates TAM gene expression through multiple signaling pathways. Specifically, TFEB upregulates suppressor of cytokine signaling 3 (SOCS3) and peroxisome proliferator-activated receptor γ (PPARγ) expression and autophagy/lysosome activities, inhibits NLRP3 (NLR Family Pyrin Domain Containing 3) inflammasome and hypoxia-inducible factor (HIF)-1α mediated hypoxia response, and thereby suppresses an array of effector molecules in TAMs including arginase 1, interleukin (IL)-10, IL-1β, IL-6 and prostaglandin E2. MΦ-specific TFEB deficiency promotes, while activation of TFEB using the natural disaccharide trehalose halts, breast tumor development by modulating TAMs. Analysis of human patient genome database reveals that expression levels of TFEB, SOCS3 and PPARγ are positive prognostic markers, while HIF-1α is a negative prognostic marker of breast cancer.ConclusionsOur study identifies TFEB as a master regulator of TAMs in breast cancer. TFEB controls TAM gene expression and function through multiple autophagy/lysosome-dependent and independent pathways. Therefore, pharmacological activation of TFEB would be a promising therapeutic approach to improve the efficacy of existing treatment including immune therapies for breast cancer by favorably modulating TAM function and the TME.

scholarly journals The Role of Estrogen in the Development of Breast Cancer

2021 ◽  
Vol 7 (2) ◽  
pp. 231-241
Author(s):  
Nikki Aldi Massardi
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptor ◽  
Tumor Growth ◽  
Endocrine Therapy ◽  
Breast Cancers ◽  
Mitogenic Effect ◽  
Human Breast ◽  
Clinically Significant ◽  
Circulating Levels

Breast cancer is a hormone-dependent disease that relies on the mitogenic effect ofestrogen to increase tumorigenesis and tumor growth. Clinically significant levels ofestrogen-α receptor (ERα) expression are seen in 80% of human breast cancers,whereas progesterone receptor is expressed in 55% of human breast cancers. Thesedata are one of the bases for the development of endocrine therapy. Endocrinetherapy is therapy that targets the pathway and synthesis of estrogen, by blocking itvia receptors, reducing circulating levels of estrogen, or suppressing estrogensynthesis in the tissues of women diagnosed with breast cancer.

scholarly journals Matriptase-2 Inhibits Breast Tumor Growth and Invasion and Correlates with Favorable Prognosis for Breast Cancer Patients

2007 ◽  
Vol 13 (12) ◽  
pp. 3568-3576 ◽  
Author(s):  
Christian Parr ◽  
Andrew J. Sanders ◽  
Gaynor Davies ◽  
Tracey Martin ◽  
Jane Lane ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Patients ◽  
Breast Tumor ◽  
Breast Cancer Patients ◽  
Favorable Prognosis ◽  
Tumor Growth And Invasion

scholarly journals In Vivo Tumor Growth Rate Measured by US in Preoperative Period and Long Term Disease Outcome in Breast Cancer Patients

PLoS ONE ◽  
2015 ◽  
Vol 10 (12) ◽  
pp. e0144144 ◽  
Author(s):  
Tae-Kyung Yoo ◽  
Jun Won Min ◽  
Min Kyoon Kim ◽  
Eunshin Lee ◽  
Jongjin Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Rate ◽  
Tumor Growth ◽  
Cancer Patients ◽  
Disease Outcome ◽  
Tumor Growth Rate ◽  
Preoperative Period ◽  
Breast Cancer Patients

scholarly journals Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation

2011 ◽  
Vol 208 (3) ◽  
pp. 479-490 ◽  
Author(s):  
Alexander Pedroza-Gonzalez ◽  
Kangling Xu ◽  
Te-Chia Wu ◽  
Caroline Aspord ◽  
Sasha Tindle ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Breast Tumor ◽  
Tumor Development ◽  
Thymic Stromal Lymphopoietin ◽  
Human Breast ◽  
Human Breast Tumor ◽  
Interleukin 13 ◽  
Th2 Inflammation

The human breast tumor microenvironment can display features of T helper type 2 (Th2) inflammation, and Th2 inflammation can promote tumor development. However, the molecular and cellular mechanisms contributing to Th2 inflammation in breast tumors remain unclear. Here, we show that human breast cancer cells produce thymic stromal lymphopoietin (TSLP). Breast tumor supernatants, in a TSLP-dependent manner, induce expression of OX40L on dendritic cells (DCs). OX40L+ DCs are found in primary breast tumor infiltrates. OX40L+ DCs drive development of inflammatory Th2 cells producing interleukin-13 and tumor necrosis factor in vitro. Antibodies neutralizing TSLP or OX40L inhibit breast tumor growth and interleukin-13 production in a xenograft model. Thus, breast cancer cell–derived TSLP contributes to the inflammatory Th2 microenvironment conducive to breast tumor development by inducing OX40L expression on DCs.

scholarly journals Association of Obesity and Breast Cancer Risk: The Role of Estrogen, Tumor Necrosis Factor-alpha, and Adiponectin as Risk factors (preliminary study)

2009 ◽  
Vol 1 (1) ◽  
pp. 45
Author(s):  
Ampi Retnowarnadi ◽  
Siti Boedina Kresno ◽  
Mansyur Arif
Keyword(s):  
Breast Cancer ◽  
Waist Circumference ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Breast Tumor ◽  
Breast Cancer Patients ◽  
High Concentration ◽  
Increased Risk ◽  
Tnf Α

BACKGROUND: Breast cancer is the most frequent cancer diagnosed among women. Many factors influence the carcinogenesis of breast cancer. The aim of this study to analyze the role of obesity (waist circumference and body mass index), serum Estradiol levels, TNF-α, and Adiponectin in the occurrence of breast cancer.METHODS: This was observational study with casecontrol design. Eleven breast cancer patients as cases and twelve Fibroadenoma Mammae (FAM) patients as controls were analyzed. The serum Estrogen, TNF-α and Adiponectin were examined in their association with breast cancer risk.RESULTS: Women with breast tumor and waist circumference > 80 cm have significantly higher breast cancer risk than women with breast tumor and waist circumference <80 cm (OR 8.75; 95% CI=1.24-61.88; p=0.029). Women with breast tumor and higher serum TNF-α levels (>2.30 pg/ml) have higher breast cancer risk (19.25 times) than women with breast tumor and have lower serum TNF-α levels (95% CI=1.77-209.55, p=0.015). Whereas, women with breast tumor and lower Adiponectin/TNF-α ratio (< 2.13) have higher breast cancer risk (22.5 times) than women with breast tumor and higher Adiponectin/TNF-α (95% CI=2.60-194.51; p=0.005).CONCLUSION: These results suggest that high concentration of serum TNF-α, waist circumference >80 cm and low Adiponectin/TNF-α ratio in women with breast tumor are significantly associated with an increased risk for breast cancer.KEYWORDS: Obesity, breast cancer, adiponectin/TNF-α ratio

scholarly journals MicroRNA-3613-3p functions as a tumor suppressor and represents a novel therapeutic target in breast cancer

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Chong Chen ◽  
Yundi Pan ◽  
Lipeng Bai ◽  
Huilin Chen ◽  
Zhaojun Duan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Patients ◽  
Cancer Genome ◽  
Breast Cancer Patients ◽  
Gain Of Function ◽  
Clinical Prognosis ◽  
Tumor Tissues ◽  
Sphere Formation

Abstract Background MicroRNAs have been reported to participate in tumorigenesis, treatment resistance, and tumor metastasis. Novel microRNAs need to be identified and investigated to guide the clinical prognosis or therapy for breast cancer. Method The copy number variations (CNVs) of MIR3613 from Cancer Genome Atlas (TCGA) or Cancer Cell Line Encyclopedia (CCLE) were analyzed, and its correlation with breast cancer subtypes or prognosis was investigated. The expression level of miR-3613-3p in tumor tissues or serum of breast cancer patients was detected using in situ hybridization and qPCR. Gain-of-function studies were performed to determine the regulatory role of miR-3613-3p on proliferation, apoptosis, and tumor sphere formation of human breast cancer cells MDA-MB-231 or MCF-7. The effects of miR-3613-3p on tumor growth or metastasis in an immunocompromised mouse model of MDA-MB-231-luciferase were explored by intratumor injection of miR-3613-3p analogue. The target genes, interactive lncRNAs, and related signaling pathways of miR-3613-3p were identified by bioinformatic prediction and 3′-UTR assays. Results We found that MIR3613 was frequently deleted in breast cancer genome and its deletion was correlated with the molecular typing, and an unfavorable prognosis in estrogen receptor-positive patients. MiR-3613-3p level was also dramatically lower in tumor tissues or serum of breast cancer patients. Gain-of-function studies revealed that miR-3613-3p could suppress proliferation and sphere formation and promote apoptosis in vitro and impeded tumor growth and metastasis in vivo. Additionally, miR-3613-3p might regulate cell cycle by targeting SMS, PAFAH1B2, or PDK3 to restrain tumor progression. Conclusion Our findings indicate a suppressive role of miR-3613-3p in breast cancer progression, which may provide an innovative marker or treatment for breast cancer patients.

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