Methyl-CpG binding domain protein 2 plays a causal role in breast cancer growth and metastasis

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.

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Obesity-Activated Lung Stromal Cells Promote Myeloid Lineage Cell Accumulation and Breast Cancer Metastasis

Cancers ◽

10.3390/cancers13051005 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1005

Author(s):

Lauren E. Hillers-Ziemer ◽

Abbey E. Williams ◽

Amanda Janquart ◽

Caitlin Grogan ◽

Victoria Thompson ◽

...

Keyword(s):

Breast Cancer ◽

Stromal Cells ◽

Cancer Metastasis ◽

Transforming Growth Factor ◽

Breast Cancer Metastasis ◽

Tumor Formation ◽

Obese Mouse ◽

Obese Mice ◽

Myeloid Lineage ◽

Primary Tumors

Obesity is correlated with increased incidence of breast cancer metastasis; however, the mechanisms underlying how obesity promotes metastasis are unclear. In a diet-induced obese mouse model, obesity enhanced lung metastasis in both the presence and absence of primary mammary tumors and increased recruitment of myeloid lineage cells into the lungs. In the absence of tumors, obese mice demonstrated increased numbers of myeloid lineage cells and elevated collagen fibers within the lung stroma, reminiscent of premetastatic niches formed by primary tumors. Lung stromal cells isolated from obese tumor-naïve mice showed increased proliferation, contractility, and expression of extracellular matrix, inflammatory markers and transforming growth factor beta-1 (TGFβ1). Conditioned media from lung stromal cells from obese mice promoted myeloid lineage cell migration in vitro in response to colony-stimulating factor 2 (CSF2) expression and enhanced invasion of tumor cells. Together, these results suggest that prior to tumor formation, obesity alters the lung microenvironment, creating niches conducive to metastatic growth.

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CXCR2: A Novel Mediator of Mammary Tumor Bone Metastasis

International Journal of Molecular Sciences ◽

10.3390/ijms20051237 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1237 ◽

Cited By ~ 4

Author(s):

Bhawna Sharma ◽

Kalyan Nannuru ◽

Sugandha Saxena ◽

Michelle Varney ◽

Rakesh Singh

Keyword(s):

Breast Cancer ◽

Bone Metastasis ◽

Tumor Cell ◽

Cancer Patients ◽

Mammary Tumor ◽

Critical Role ◽

Breast Cancer Patients ◽

Mammary Tumor Cell ◽

Primary Tumors

Most breast cancer patients die due to bone metastasis. Although metastasis accounts for 5% of the breast cancer cases, it is responsible for most of the deaths. Sometimes even before the detection of a primary tumor, most of the patients have bone and lymph node metastasis. Moreover, at the time of death, breast cancer patients have the bulk of the tumor burden in their bones. Therapy options are available for the treatment of primary tumors, but there are minimal options for treating breast cancer patients who have bone metastasis. C-X-C motif chemokine receptor type 2 (CXCR2) receptor-mediated signaling has been shown to play a critical role during bone-related inflammations and its ligands C-X-C motif chemokine ligand 6 (CXCL6) and 8 (CXCL8) aid in the resorption of bone during bone metastasis. In this study, we tested the hypothesis that CXCR2 contributes to mammary tumor-induced osteolysis and bone metastasis. In the present study, we examined the role of both tumor cell-derived and host-derived CXCR2 in influencing mammary tumor cell bone metastasis. For understanding the role of tumor cell-derived CXCR2, we utilized Cl66 CXCR2 knockdown (Cl66-shCXCR2) and Cl66-Control cells (Cl66-Control) and observed a significant decrease in tumor growth and tumor-induced osteolysis in Cl66-shCXCR2 cells in comparison with the Cl66-Control cells. Next, for understanding the role of host-derived CXCR2, we utilized mice with genomic knockdown of CXCR2 (Cxcr2−/−) and injected Cl66-Luciferase (Cl66-Luc) or 4T1-Luciferase (4T1-Luc) cells. We observed decreased bone destruction and metastasis in the bone of Cxcr2−/− mice. Our data suggest the importance of both tumor cell- and host-derived CXCR2 signaling in the bone metastasis of breast cancer cells.

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Assessment of the WAP-Myc mouse mammary tumor model for spontaneous metastasis

Scientific Reports ◽

10.1038/s41598-020-75411-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Begüm Utz ◽

Rita Turpin ◽

Johanna Lampe ◽

Jeroen Pouwels ◽

Juha Klefström

Keyword(s):

Breast Cancer ◽

Mammary Tumor ◽

Tumor Model ◽

Primary Tumors ◽

T Cell Infiltration ◽

Cancer Models ◽

Mouse Mammary Tumor ◽

Mammary Tumor Model ◽

Metastatic Process ◽

Mouse Mammary Tumor Model

Abstract Breast cancer is the most common form of cancer in women. Despite significant therapeutic advances in recent years, breast cancer also still causes the greatest number of cancer-related deaths in women, the vast majority of which (> 90%) are caused by metastases. However, very few mouse mammary cancer models exist that faithfully recapitulate the multistep metastatic process in human patients. Here we assessed the suitability of a syngrafting protocol for a Myc-driven mammary tumor model (WAP-Myc) to study autochthonous metastasis. A moderate but robust spontaneous lung metastasis rate of around 25% was attained. In addition, increased T cell infiltration was observed in metastatic tumors compared to donor and syngrafted primary tumors. Thus, the WAP-Myc syngrafting protocol is a suitable tool to study the mechanisms of metastasis in MYC-driven breast cancer.

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Sulforaphane Diminishes the Formation of Mammary Tumors in Rats Exposed to 17β-Estradiol

Nutrients ◽

10.3390/nu12082282 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2282

Author(s):

Dushani L. Palliyaguru ◽

Li Yang ◽

Dionysios V. Chartoumpekis ◽

Stacy G. Wendell ◽

Marco Fazzari ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Mammary Tumor ◽

Acid Metabolism ◽

Slow Release ◽

Mammary Tumorigenesis ◽

Mammary Glands ◽

Tumor Formation ◽

Serum Free Fatty Acids ◽

17Β Estradiol

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.

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Abstract 4813: DNA methylation of tumor suppressor and metastasis suppressor genes in primary tumors, circulating tumor cells and cell free DNA in the same breast cancer patients

10.1158/1538-7445.am2014-4813 ◽

2014 ◽

Cited By ~ 1

Author(s):

Maria Chimonidou ◽

Areti Strati ◽

Nikos Malamos ◽

Vassilis Georgoulias ◽

Evi Lianidou

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

Tumor Suppressor ◽

Cancer Patients ◽

Tumor Cells ◽

Metastasis Suppressor ◽

Breast Cancer Patients ◽

Primary Tumors ◽

Metastasis Suppressor Genes ◽

Free Dna

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Hyperinsulinemia promotes metastasis to the lung in a mouse model of Her2-mediated breast cancer

Endocrine Related Cancer ◽

10.1530/erc-12-0333 ◽

2013 ◽

Vol 20 (3) ◽

pp. 391-401 ◽

Cited By ~ 34

Author(s):

Rosalyn D Ferguson ◽

Emily J Gallagher ◽

Dara Cohen ◽

Aviva Tobin-Hess ◽

Nyosha Alikhani ◽

...

Keyword(s):

Breast Cancer ◽

Mouse Model ◽

Lung Metastases ◽

Breast Cancer Incidence ◽

Mesenchymal Cells ◽

Tumor Formation ◽

Metastatic Progression ◽

Primary Tumors ◽

Mesenchymal Transition ◽

Incidence And Mortality

The Her2 oncogene is expressed in ∼25% of human breast cancers and is associated with metastatic progression and poor outcome. Epidemiological studies report that breast cancer incidence and mortality rates are higher in women with type 2 diabetes. Here, we use a mouse model of Her2-mediated breast cancer on a background of hyperinsulinemia to determine how elevated circulating insulin levels affect Her2-mediated primary tumor growth and lung metastasis. Hyperinsulinemic (MKR+/+) mice were crossed with doxycycline-inducible Neu-NT (MTB/TAN) mice to produce the MTB/TAN/MKR+/+ mouse model. Both MTB/TAN and MTB/TAN/MKR+/+ mice were administered doxycycline in drinking water to induce Neu-NT mammary tumor formation. In tumor tissues removed at 2, 4, and 6 weeks of Neu-NT overexpression, we observed increased tumor mass and higher phosphorylation of the insulin receptor/IGF1 receptor, suggesting that activation of these receptors in conditions of hyperinsulinemia could contribute to the increased growth of mammary tumors. After 12 weeks on doxycycline, although no further increase in tumor weight was observed in MTB/TAN/MKR+/+ compared with MTB/TAN mice, the number of lung metastases was significantly higher in MTB/TAN/MKR+/+ mice compared with controls (MTB/TAN/MKR+/+ 16.41±4.18 vs MTB/TAN 5.36±2.72). In tumors at the 6-week time point, we observed an increase in vimentin, a cytoskeletal protein and marker of mesenchymal cells, associated with epithelial-to-mesenchymal transition and cancer-associated fibroblasts. We conclude that hyperinsulinemia in MTB/TAN/MKR+/+ mice resulted in larger primary tumors, with more mesenchymal cells and therefore more aggressive tumors with more numerous pulmonary metastases.

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