scholarly journals Ron Receptor Signaling Augments Mammary Tumor Formation and Metastasis in a Murine Model of Breast Cancer

2005 ◽  
Vol 65 (4) ◽  
pp. 1285-1293 ◽  
Author(s):  
Belinda E. Peace ◽  
Kenya Toney-Earley ◽  
Margaret H. Collins ◽  
Susan E. Waltz
2020 ◽  
Author(s):  
Niaz Mahmood ◽  
Ani Arakelian ◽  
Moshe Szyf ◽  
Shafaat A. Rabbani

AbstractMethyl-CpG-binding domain protein 2 (Mbd2), a reader of DNA-methylation, has been implicated in the progression of several types of malignancies, including breast cancer. To test whether Mbd2, which is overexpressed in human breast cancer samples and in MMTV-PyMT mammary pads, plays a causal role in mammary tumor growth and metastasis we depleted Mbd2 in transgenic MMTV-PyMT model of breast cancer by cross-breeding with Mbd2 knockout mice to generate heterozygous (PyMT;Mbd2+/-) and homozygous (PyMT;Mbd2-/-) animals. We found that Mbd2 depletion caused a gene dose-dependent delay in mammary tumor formation, reduced primary tumor burden, and lung metastasis at the experimental endpoint. In addition, animals from the PyMT;Mbd2-/- group survived significantly longer compared to the wildtype (PyMT;Mbd2+/+) and PyMT;Mbd2+/- arms. Transcriptomic and proteomic analyses of the primary tumors obtained from PyMT;Mbd2+/+ and PyMT;Mbd2+/- groups revealed that Mbd2 depletion alters several key determinants of the molecular signaling networks related to tumorigenesis and metastasis, which thereby demonstrate that Mbd2 is regulating transcriptional programs critical for breast cancer. To our knowledge, this is the first study demonstrating a causal role for a DNA-methylation reader in breast cancer. Results from this study will provide the rationale for further development of first-in-class targeted epigenetic therapies against Mbd2 to inhibit the progression of breast and other common cancers.


Nutrients ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2282
Author(s):  
Dushani L. Palliyaguru ◽  
Li Yang ◽  
Dionysios V. Chartoumpekis ◽  
Stacy G. Wendell ◽  
Marco Fazzari ◽  
...  

Elevated levels of estrogen are a risk factor for breast cancer. In addition to inducing DNA damage, estrogens can enhance cell proliferation as well as modulate fatty acid metabolism that collectively contributes to mammary tumorigenesis. Sulforaphane (SFN) is an isothiocyanate derived from broccoli that is currently under evaluation in multiple clinical trials for prevention of several diseases, including cancer. Previous studies showed that SFN suppressed DNA damage and lipogenesis pathways. Therefore, we hypothesized that administering SFN to animals that are co-exposed to 17β-estradiol (E2) would prevent mammary tumor formation. In our study, 4–6 week old female August Copenhagen Irish rats were implanted with slow-release E2 pellets (3 mg x 3 times) and gavaged 3x/week with either vehicle or 100 μmol/kg SFN for 56 weeks. SFN-treated rats were protected significantly against mammary tumor formation compared to vehicle controls. Mammary glands of SFN-treated rats showed decreased DNA damage while serum free fatty acids and triglyceride species were 1.5 to 2-fold lower in SFN-treated rats. Further characterization also showed that SFN diminished expression of enzymes involved in mammary gland lipogenesis. This study indicated that SFN protects against breast cancer development through multiple potential mechanisms in a clinically relevant hormonal carcinogenesis model.


2012 ◽  
Vol 20 (1) ◽  
pp. 39-51 ◽  
Author(s):  
Nikki A Ford ◽  
Nomeli P Nunez ◽  
Valerie B Holcomb ◽  
Stephen D Hursting

Luminal breast tumors with little or no estrogen receptor α expression confer poor prognosis. Using the Met1 murine model of luminal breast cancer, we characterized the IGF1-dependency of diet-induced obesity (DIO) and calorie restriction (CR) effects on tumor growth, growth factor signaling, epithelial-to-mesenchymal transition (EMT), and chemokine expression. Liver-specific IGF1-deficient (LID) and littermate control (LC) mice were administered control, DIO, or 30% CR diets for 3 months before orthotopic injection of Met1 cells. Tumors grew for 1 month and then were assessed for Akt pathway activation and mRNA expression of chemokine and EMT constituents. LID mice, regardless of diet, displayed reduced Met1 tumor growth and downregulated Akt, EMT, and chemokine pathways. CR, relative to control, reduced serum IGF1 and Met1 tumor growth in LC (but not LID) mice. DIO, relative to control, increased Met1 tumor growth and chemokine expression in LID mice, and had no effect on serum IGF1 or pAkt or cyclin D1 expression in either genotype. Thus, circulating IGF1 (in association with Akt, EMT, and chemokines) regulated Met1 tumor growth. While the anticancer effects of CR were largely IGF1-dependent, the procancer effects of DIO manifested only when circulating IGF1 levels were low. Thus, in a murine model of luminal breast cancer, IGF1 and its downstream signaling pathway, EMT, and chemokines present possible mechanistic regulatory targets. Transplanted MMTV1 Wnt1 mammary tumor growth was also reduced in LID mice, relative to LC mice, suggesting that the IGF1 effects on mammary tumor growth are not limited to Met1 tumors.


2013 ◽  
Vol 110 (21) ◽  
pp. 8632-8637 ◽  
Author(s):  
C. Bowman-Colin ◽  
B. Xia ◽  
S. Bunting ◽  
C. Klijn ◽  
R. Drost ◽  
...  

Author(s):  
Merve Erkisa ◽  
Nazlihan Aztopal ◽  
Elif Erturk ◽  
Engin Ulukaya ◽  
Veysel T. Yilmaz ◽  
...  

Background: Cancer stem cells (CSC) are subpopulation within the tumor that acts a part in the initiation, progression, recurrence, resistance to drugs and metastasis of cancer. It is well known that epigenetic changes lead to tumor formation in cancer stem cells and show drug resistance. Epigenetic modulators and /or their combination with different agents have been used in cancer therapy. Objective: In our study we scope out the effects of combination of a histone deacetylases inhibitor, valproic acid (VPA), and Cu(II) complex [Cu(barb-κN)(barb-κ2N,O)(phen-κN,N’)]·H2O] on cytotoxicity/apoptosis in a stem-cell enriched population (MCF-7s) obtained from parental breast cancer cell line (MCF-7). Methods: Viability of the cells was measured by the ATP assay. Apoptosis was elucidated via the assessment of caspase-cleaved cytokeratin 18 (M30 ELISA) and a group of flow cytometry analysis (caspase 3/7 activity, phosphatidylserine translocation by annexin V-FITC assay, DNA damage and oxidative stress) and 2ˈ,7ˈ–dichlorofluorescein diacetate staining. Results: The VPA combined with Cu(II) complex showed anti proliferative activity on MCF-7s cells in a dose- and time-dependently. Treatment with combination of 2.5 mM VPA and 3.12 μM Cu(II) complex induces oxidative stress in a time-dependent manner, as well as apoptosis that is evidenced by the increase in caspase 3/7 activity, positive annexin-V-FITC, and increase in M30 levels. Conclusion: The results suggest that the combination therapy induces apoptosis following increased oxidative stress, thereby making it a possible promising therapeutic strategy that further analysis is required.


Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 308
Author(s):  
Marion Buffard ◽  
Aurélien Naldi ◽  
Gilles Freiss ◽  
Marcel Deckert ◽  
Ovidiu Radulescu ◽  
...  

Spleen tyrosine kinase (SYK) can behave as an oncogene or a tumor suppressor, depending on the cell and tissue type. As pharmacological SYK inhibitors are currently evaluated in clinical trials, it is important to gain more information on the molecular mechanisms underpinning these opposite roles. To this aim, we reconstructed and compared its signaling networks using phosphoproteomic data from breast cancer and Burkitt lymphoma cell lines where SYK behaves as a tumor suppressor and promoter. Bioinformatic analyses allowed for unveiling the main differences in signaling pathways, network topology and signal propagation from SYK to its potential effectors. In breast cancer cells, the SYK target-enriched signaling pathways included intercellular adhesion and Hippo signaling components that are often linked to tumor suppression. In Burkitt lymphoma cells, the SYK target-enriched signaling pathways included molecules that could play a role in SYK pro-oncogenic function in B-cell lymphomas. Several protein interactions were profoundly rewired in the breast cancer network compared with the Burkitt lymphoma network. These data demonstrate that proteomic profiling combined with mathematical network modeling allows untangling complex pathway interplays and revealing difficult to discern interactions among the SYK pathways that positively and negatively affect tumor formation and progression.


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