Frankincense, pine needle and geranium essential oils suppress tumor progression through the regulation of the AMPK/mTOR pathway in breast cancer

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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Faculty Opinions recommendation of The Diasporin Pathway: a tumor progression-related transcriptional network that predicts breast cancer survival.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1120417.576610 ◽

2008 ◽

Author(s):

David Beier

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Cancer Survival ◽

Breast Cancer Survival ◽

Transcriptional Network

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Chitosan Oligosaccharides Inhibit Tumor Progression and Induce Autophagy Through Activation of the p53/mTOR Pathway in Osteosarcoma

SSRN Electronic Journal ◽

10.2139/ssrn.3457401 ◽

2019 ◽

Author(s):

Zhen Pan ◽

Xiao-juan Wei ◽

Shi-jie Li ◽

Hua Guo ◽

Dong-dong Cheng ◽

...

Keyword(s):

Tumor Progression ◽

Mtor Pathway ◽

Chitosan Oligosaccharides

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Iron-Bound Lipocalin-2 from Tumor-Associated Macrophages Drives Breast Cancer Progression Independent of Ferroportin

Metabolites ◽

10.3390/metabo11030180 ◽

2021 ◽

Vol 11 (3) ◽

pp. 180

Author(s):

Christina Mertens ◽

Matthias Schnetz ◽

Claudia Rehwald ◽

Stephan Grein ◽

Eiman Elwakeel ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Tumor Cells ◽

Cancer Progression ◽

Lung Metastases ◽

Expression Profiles ◽

The Cancer Genome Atlas ◽

Lipocalin 2 ◽

Tumor Associated Macrophages

Macrophages supply iron to the breast tumor microenvironment by enforced secretion of lipocalin-2 (Lcn-2)-bound iron as well as the increased expression of the iron exporter ferroportin (FPN). We aimed at identifying the contribution of each pathway in supplying iron for the growing tumor, thereby fostering tumor progression. Analyzing the expression profiles of Lcn-2 and FPN using the spontaneous polyoma-middle-T oncogene (PyMT) breast cancer model as well as mining publicly available TCGA (The Cancer Genome Atlas) and GEO Series(GSE) datasets from the Gene Expression Omnibus database (GEO), we found no association between tumor parameters and Lcn-2 or FPN. However, stromal/macrophage-expression of Lcn-2 correlated with tumor onset, lung metastases, and recurrence, whereas FPN did not. While the total iron amount in wildtype and Lcn-2−/− PyMT tumors showed no difference, we observed that tumor-associated macrophages from Lcn-2−/− compared to wildtype tumors stored more iron. In contrast, Lcn-2−/− tumor cells accumulated less iron than their wildtype counterparts, translating into a low migratory and proliferative capacity of Lcn-2−/− tumor cells in a 3D tumor spheroid model in vitro. Our data suggest a pivotal role of Lcn-2 in tumor iron-management, affecting tumor growth. This study underscores the role of iron for tumor progression and the need for a better understanding of iron-targeted therapy approaches.

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m6A-induced LINC00958 promotes breast cancer tumorigenesis via the miR-378a-3p/YY1 axis

Cell Death Discovery ◽

10.1038/s41420-020-00382-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Dongwen Rong ◽

Qian Dong ◽

Huajun Qu ◽

Xinna Deng ◽

Fei Gao ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Human Breast Cancer ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Human Breast ◽

Transcript Stability ◽

Rna Transcript ◽

Insight Into ◽

Competitive Endogenous Rna

AbstractIncreasing evidence demonstrates that long noncoding RNAs (lncRNAs) play critical roles in human breast cancer (BC) tumorigenesis. However, the mechanisms by which lncRNA and N6-methyladenosine (m6A) regulate BC tumorigenesis are still unclear. In the present research, LINC00958 was markedly overexpressed in BC tissue and cells, and LINC00958 upregulation promoted the tumor progression of BC cells. Mechanistically, m6A methyltransferase-like 3 (METTL3) gave rise to the upregulation of LINC00958 by promoting its RNA transcript stability. Moreover, LINC00958 acted as a competitive endogenous RNA for miR-378a-3p to promote YY1. Overall, these data provide novel insight into how m6A-mediated LINC00958 regulates BC tumorigenesis.

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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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Stromal CCL5 Promotes Breast Cancer Progression by Interacting with CCR3 in Tumor Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22041918 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1918

Author(s):

Mio Yamaguchi ◽

Kiyoshi Takagi ◽

Koki Narita ◽

Yasuhiro Miki ◽

Yoshiaki Onodera ◽

...

Keyword(s):

Breast Cancer ◽

Breast Carcinoma ◽

Tumor Progression ◽

Tumor Cells ◽

Cancer Progression ◽

Stromal Cells ◽

Human Breast Carcinoma ◽

Breast Cancer Patients ◽

Breast Carcinomas ◽

Human Breast

Chemokines secreted from stromal cells have important roles for interactions with carcinoma cells and regulating tumor progression. C-C motif chemokine ligand (CCL) 5 is expressed in various types of stromal cells and associated with tumor progression, interacting with C-C chemokine receptor (CCR) 1, 3 and 5 expressed in tumor cells. However, the expression on CCL5 and its receptors have so far not been well-examined in human breast carcinoma tissues. We therefore immunolocalized CCL5, as well as CCR1, 3 and 5, in 111 human breast carcinoma tissues and correlated them with clinicopathological characteristics. Stromal CCL5 immunoreactivity was significantly correlated with the aggressive phenotype of breast carcinomas. Importantly, this tendency was observed especially in the CCR3-positive group. Furthermore, the risk of recurrence was significantly higher in the patients with breast carcinomas positive for CCL5 and CCR3 but negative for CCR1 and CCR5, as compared with other patients. In summary, the CCL5-CCR3 axis might contribute to a worse prognosis in breast cancer patients, and these findings will contribute to a better understanding of the significance of the CCL5/CCRs axis in breast carcinoma microenvironment.

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