Mammalian target of rapamycin inhibition abrogates insulin-mediated mammary tumor progression in type 2 diabetes

Type 2 diabetes increases breast cancer risk and mortality, and hyperinsulinemia is a major mediator of this effect. The mammalian target of rapamycin (mTOR) is activated by insulin and is a key regulator of mammary tumor progression. Pharmacological mTOR inhibition suppresses tumor growth in numerous mammary tumor models in the non-diabetic setting. However, the role of the mTOR pathway in type 2 diabetes-induced tumor growth remains elusive. Herein, we investigated whether the mTOR pathway is implicated in insulin-induced mammary tumor progression in a transgenic mouse model of type 2 diabetes (MKR mice) and evaluated the impact of mTOR inhibition on the diabetic state. Mammary tumor progression was studied in the double transgenic MMTV-Polyoma Virus middle T antigen (PyVmT)/MKR mice and by orthotopic inoculation of PyVmT- and Neu/ErbB2-driven mammary tumor cells (Met-1 and MCNeuA cells respectively). mTOR inhibition by rapamycin markedly suppressed tumor growth in both wild-type and MKR mice. In diabetic animals, however, the promoting action of insulin on tumor growth was completely blunted by rapamycin, despite a worsening of the carbohydrate and lipid metabolism. Taken together, pharmacological mTOR blockade is sufficient to abrogate mammary tumor progression in the setting of hyperinsulinemia, and thus mTOR inhibitors may be an attractive therapeutic modality for breast cancer patients with type 2 diabetes. Careful monitoring of the metabolic state, however, is important as dose adaptations of glucose- and/or lipid-lowering therapy might be necessary.

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Insulin-Sensitizing Therapy Attenuates Type 2 Diabetes-Mediated Mammary Tumor Progression

Diabetes ◽

10.2337/db09-1291 ◽

2009 ◽

Vol 59 (3) ◽

pp. 686-693 ◽

Cited By ~ 69

Author(s):

Y. Fierz ◽

R. Novosyadlyy ◽

A. Vijayakumar ◽

S. Yakar ◽

D. LeRoith

Keyword(s):

Type 2 Diabetes ◽

Tumor Progression ◽

Mammary Tumor ◽

Mammary Tumor Progression

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mTOR Inhibition Abrogates Insulin Mediated Mammary Tumor Progression in Type 2 Diabetic Mice.

10.1210/endo-meetings.2010.part2.or.or12-4 ◽

2010 ◽

pp. OR12-4-OR12-4

Author(s):

YC Fierz ◽

R Novosyadlyy ◽

A Vijayakumar ◽

D LeRoith

Keyword(s):

Tumor Progression ◽

Mammary Tumor ◽

Diabetic Mice ◽

Mtor Inhibition ◽

Type 2 Diabetic ◽

Mammary Tumor Progression

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P35 Reduced serum IGF-1 levels do not affect insulin-mediated mammary tumor progression in type 2 diabetes

Growth Hormone & IGF Research ◽

10.1016/s1096-6374(10)70135-0 ◽

2010 ◽

Vol 20 ◽

pp. S52

Author(s):

Y.C. Fierz ◽

R. Novosyadlyy ◽

A. Vijayakumar ◽

S. Yakar ◽

D. LeRoith

Keyword(s):

Type 2 Diabetes ◽

Tumor Progression ◽

Mammary Tumor ◽

Mammary Tumor Progression

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Cholesteryl Ester Promotes Mammary Tumor Growth in MMTV-PyMT Mice and Activates Akt-mTOR Pathway in Tumor Cells

Biomolecules ◽

10.3390/biom11060853 ◽

2021 ◽

Vol 11 (6) ◽

pp. 853

Author(s):

Lengyun Wei ◽

Xuyang Lu ◽

Shengmei Weng ◽

Shenglong Zhu ◽

Yongquan Chen

Keyword(s):

Tumor Growth ◽

Cholesteryl Ester ◽

Tumor Progression ◽

Mammary Tumor ◽

Causal Effect ◽

Mtor Pathway ◽

Breast Tumor Cell ◽

Mammary Tumor Growth ◽

Mammary Tumor Progression ◽

Mcf 7

The association between intratumoral cholesteryl ester (CE) and tumor progression has been reported previously. The objective of our study was to investigate a causal effect of CE on mammary tumor progression. Using MMTV-PyMT (MMTV-polyoma virus middle T) transgenic mice and breast tumor cell MCF-7, we show that both exogenous and endogenous CE can increase mammary tumor growth, that CE upregulates the AKT/mTOR pathway, and that CE synthesis blockade suppresses this signaling pathway. Our data suggest that SOAT1, a sterol O-acyltransferase, may be a potential target for the treatment of breast cancer.

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Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22105207 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5207

Author(s):

Chi Yan ◽

Jinming Yang ◽

Nabil Saleh ◽

Sheau-Chiann Chen ◽

Gregory D. Ayers ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Tumor Growth ◽

Cd8 T Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Mtor Pathway ◽

Complete Regression ◽

Mtor Inhibition

Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. Results: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. Conclusion: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.

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Chronic Stress Exposure Suppresses Mammary Tumor Growth and Reduces Circulating Exosome TGF-β Content via β-Adrenergic Receptor Signaling in MMTV-PyMT Mice

Breast Cancer Basic and Clinical Research ◽

10.1177/1178223420931511 ◽

2020 ◽

Vol 14 ◽

pp. 117822342093151 ◽

Cited By ~ 1

Author(s):

Ryan P Dawes ◽

Kathleen A Burke ◽

Daniel K Byun ◽

Zhou Xu ◽

Petr Stastka ◽

...

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Tumor Growth ◽

Tumor Progression ◽

Mammary Tumor ◽

Adrenergic Receptor ◽

Caspase 3 ◽

Tumor Burden ◽

Stress Exposure ◽

Metastatic Lesions

Preclinical models of breast cancer have established mechanistic links between psychological stress and cancer progression. However, epidemiological evidence linking stress and cancer is equivocal. We tested the impact of stress exposure in female mice expressing the mouse mammary tumor virus polyoma middle-T antigen (MMTV-PyMT), a spontaneous model of mammary adenocarcinoma that mimics metastatic hormone receptor–positive human breast cancer development. MMTV-PyMT mice were socially isolated at 6 to 7 weeks of age during premalignant hyperplasia. To increase the potency of the stressor, singly housed mice were exposed to acute restraint stress (2 hours per day for 3 consecutive days) at 8 to 9 weeks of age during early carcinoma. Exposure to this dual stressor activated both major stress pathways, the sympathetic nervous system and hypothalamic-pituitary-adrenal axis throughout malignant transformation. Stressor exposure reduced mammary tumor burden in association with increased tumor cleaved caspase-3 expression, indicative of increased cell apoptosis. Stress exposure transiently increased tumor vascular endothelial growth factor and reduced tumor interleukin-6, but no other significant alterations in immune/inflammation-associated chemokines and cytokines or changes in myeloid cell populations were detected in tumors. No stress-induced change in second-harmonic generation-emitting collagen, indicative of a switch to a metastasis-promoting tumor extracellular matrix, was detected. Systemic indicators of slowed tumor progression included reduced myeloid-derived suppressor cell (MDSC) frequency in lung and spleen, and decreased transforming growth factor β (TGF-β) content in circulating exosomes, nanometer-sized particles associated with tumor progression. Chronic β-adrenergic receptor (β-AR) blockade with nadolol abrogated stress-induced alterations in tumor burden and cleaved caspase-3 expression, lung MDSC frequency, and exosomal TGF-β content. Despite the evidence for reduced tumor growth, metastatic lesions in the lung were not altered by stress exposure. Unexpectedly, β-blockade in nonstressed mice increased lung metastatic lesions and splenic MDSC frequency, suggesting that in MMTV-PyMT mice, β-AR activation also inhibits tumor progression in the absence of stress exposure. Together, these results suggest stress exposure can act through β-AR signaling to slow primary tumor growth in MMTV-PyMT mice.

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