scholarly journals Targeting the Aryl Hydrocarbon Receptor Signaling Pathway in Breast Cancer Development

2021 ◽  
Vol 12 ◽  
Author(s):  
Christoph F. A. Vogel ◽  
Gwendal Lazennec ◽  
Sarah Y. Kado ◽  
Carla Dahlem ◽  
Yi He ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Aryl Hydrocarbon Receptor ◽  
Tumor Cells ◽  
Mammary Tumor ◽  
T Antigen ◽  
Functional Restoration ◽  
Repressor Protein ◽  
Mammary Tumor Cells ◽  
Aryl Hydrocarbon ◽  
The Impact

Activation of the aryl hydrocarbon receptor (AhR) through environmental exposure to known human carcinogens including dioxins can lead to the promotion of breast cancer. While the repressor protein of the AhR (AhRR) blocks the canonical AhR pathway, the function of AhRR in the development of breast cancer is not well-known. In the current study we examined the impact of suppressing AhR activity using its dedicated repressor protein AhRR. AhRR is a putative tumor suppressor and is silenced in several cancer types, including breast, where its loss correlates with shorter patient survival. Using the AhRR transgenic mouse, we demonstrate that AhRR overexpression opposes AhR-driven and inflammation-induced growth of mammary tumors in two different murine models of breast cancer. These include a syngeneic model using E0771 mammary tumor cells as well as the Polyoma Middle T antigen (PyMT) transgenic model. Further AhRR overexpression or knockout of AhR in human breast cancer cells enhanced apoptosis induced by chemotherapeutics and inhibited the growth of mouse mammary tumor cells. This study provides the first in vivo evidence that AhRR suppresses mammary tumor development and suggests that strategies which lead to its functional restoration and expression may have therapeutic benefit.

scholarly journals Involvement of Insulin Receptor Substrate 2 in Mammary Tumor Metastasis

2004 ◽  
Vol 24 (22) ◽  
pp. 9726-9735 ◽  
Author(s):  
Julie A. Nagle ◽  
Zhefu Ma ◽  
Maura A. Byrne ◽  
Morris F. White ◽  
Leslie M. Shaw
Keyword(s):  
Breast Cancer ◽  
Insulin Receptor ◽  
Tumor Cells ◽  
Mammary Tumor ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
T Antigen ◽  
Insulin Receptor Substrate ◽  
Mammary Tumor Cells

ABSTRACT The insulin receptor substrate (IRS) proteins are adaptor molecules that integrate signals generated by receptors that are implicated in human breast cancer. We investigated the specific contribution of IRS-2 to mammary tumor progression using transgenic mice that express the polyoma virus middle T antigen (PyV-MT) in the mammary gland and IRS-2-null (IRS-2−/−) mice. PyV-MT-induced tumor initiation and growth were similar in wild-type (WT) and IRS-2−/− mice. However, the latency and incidence of metastasis were significantly decreased in the absence of IRS-2 expression. The contribution of IRS-2 to metastasis is intrinsic to the tumor cells, because IRS-2−/− mammary tumor cells did not metastasize when grown orthotopically in the mammary fat pads of WT mice. WT and IRS-2−/− tumors contained similar numbers of mitotic cells, but IRS-2−/− tumors had a higher incidence of apoptosis than did WT tumors. In vitro, IRS-2−/− mammary tumor cells were less invasive and more apoptotic in response to growth factor deprivation than their WT counterparts. In contrast, IRS-1−/− tumor cells, which express only IRS-2, were highly invasive and were resistant to apoptotic stimuli. Collectively, our findings reveal an important contribution of IRS-2 to breast cancer metastasis.

scholarly journals The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells

Oncogene ◽  
2005 ◽  
Vol 24 (53) ◽  
pp. 7869-7881 ◽  
Author(s):  
Xinhai Yang ◽  
Donghui Liu ◽  
Tessa J Murray ◽  
Geoffrey C Mitchell ◽  
Eli V Hesterman ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Tumor Cells ◽  
Mammary Tumor ◽  
Mammary Tumor Cells ◽  
Aryl Hydrocarbon ◽  
Human Mammary Tumor Cells

scholarly journals BSCI-11. STROMAL PLATELET DERIVED GROWTH FACTOR RECEPTOR-β (PDGFRβ) PROMOTES BREAST CANCER BRAIN METASTASIS

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i3-i3
Author(s):  
Katie Thies ◽  
Anisha Hammer ◽  
Blake Hildreth ◽  
Luke Russell ◽  
Steven Sizemore ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Tumor Cells ◽  
Mammary Tumor ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Mammary Tumor Cells ◽  
The Brain

Abstract Stromal platelet-derived growth factor receptor-beta (PDGFRβ) has emerged as an actionable mediator of breast tumor-stromal communication. As a receptor tyrosine kinase, PDGFRβ is activated by its ligand, PDGFB, which is released by neighboring tumor epithelium and endothelium. However, how PDGF signaling mediates breast cancer (BC) initiation, progression, and metastasis remains unclear. To evaluate PDGFRβ in this disease, we developed a mouse model of stromal-specific PDGFRβ activation using the Fsp-cre transgene previously published by our group. Mesenchymal-specific activation of PDGFRβ promotes preferential experimental brain metastasis of PDGFB-expressing mammary tumor cells when injected intravenously and accelerates intracranial tumor growth of these cells. Mammary tumor cells expressing low levels of PDGFB do not exhibit a similar increase in brain metastases in PDGFRβ mutant mice. To our knowledge, this is the first example where genetic manipulation of the stroma leads to an increased incidence of BCBM. Our pre-clinical data suggests that primary breast tumors that express high PDGFB could preferentially metastasize to the brain. To test this in patients, we analyzed PDGFB protein expression in a tissue microarray comprised of HER2-positive and triple negative BC primary tumors. While high PDGFB did not correlate with site-independent metastatic recurrence, it was prognostic of brain metastasis, mirroring our mouse data. Our findings suggest that high primary tumor PDGFB expression defines a subset of BC patients predisposed to brain metastases. These patients may benefit from therapeutic intervention of PDGFRβ signaling. To test this pre-clinically, we treated mice harboring intracranial tumors with the PDGFR-specific inhibitor, crenolanib. Excitingly, crenolanib treatment significantly inhibited the brain tumor burden in these mice. Combined, our findings (1) advocate that primary tumor expression of PDGFB is a novel prognostic biomarker for the development of BCBM and (2) support clinical trial evaluation of PDGFR inhibitors for the prevention and treatment of BCBM.

In vitro and in vivo assessments of two novel hydrazide compounds against breast cancer as well as mammary tumor cells

2017 ◽  
Vol 79 (6) ◽  
pp. 1195-1203 ◽  
Author(s):  
Elham Mousavi ◽  
Shahrzad Tavakolfar ◽  
Ali Almasirad ◽  
Zahra Kooshafar ◽  
Soudeh Dehghani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Mammary Tumor ◽  
Mammary Tumor Cells

scholarly journals Parsing β-catenin’s cell adhesion and Wnt signaling functions in malignant mammary tumor progression

2021 ◽  
Vol 118 (34) ◽  
pp. e2020227118
Author(s):  
David Buechel ◽  
Nami Sugiyama ◽  
Natalia Rubinstein ◽  
Meera Saxena ◽  
Ravi K. R. Kalathur ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Adhesion ◽  
Wnt Signaling ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Mammary Tumor ◽  
Dual Function ◽  
Mammary Tumor Cells ◽  
Cell Cell

During malignant progression, epithelial cancer cells dissolve their cell–cell adhesion and gain invasive features. By virtue of its dual function, β-catenin contributes to cadherin-mediated cell–cell adhesion, and it determines the transcriptional output of Wnt signaling: via its N terminus, it recruits the signaling coactivators Bcl9 and Pygopus, and via the C terminus, it interacts with the general transcriptional machinery. This duality confounds the simple loss-of-function analysis of Wnt signaling in cancer progression. In many cancer types including breast cancer, the functional contribution of β-catenin’s transcriptional activities, as compared to its adhesion functions, to tumor progression has remained elusive. Employing the mouse mammary tumor virus (MMTV)–PyMT mouse model of metastatic breast cancer, we compared the complete elimination of β-catenin with the specific ablation of its signaling outputs in mammary tumor cells. Notably, the complete lack of β-catenin resulted in massive apoptosis of mammary tumor cells. In contrast, the loss of β-catenin’s transcriptional activity resulted in a reduction of primary tumor growth, tumor invasion, and metastasis formation in vivo. These phenotypic changes were reflected by stalled cell cycle progression and diminished epithelial–mesenchymal transition (EMT) and cell migration of breast cancer cells in vitro. Transcriptome analysis revealed subsets of genes which were specifically regulated by β-catenin’s transcriptional activities upon stimulation with Wnt3a or during TGF-β–induced EMT. Our results uncouple the signaling from the adhesion function of β-catenin and underline the importance of Wnt/β-catenin–dependent transcription in malignant tumor progression of breast cancer.

scholarly journals MMTV-PyMT and Derived Met-1 Mouse Mammary Tumor Cells as Models for Studying the Role of the Androgen Receptor in Triple-Negative Breast Cancer Progression

2017 ◽  
Vol 8 (2) ◽  
pp. 69-77 ◽  
Author(s):  
Jessica L. Christenson ◽  
Kiel T. Butterfield ◽  
Nicole S. Spoelstra ◽  
John D. Norris ◽  
Jatinder S. Josan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Mammary Tumor ◽  
Triple Negative ◽  
Mammary Tumor Cells ◽  
Mouse Mammary Tumor

scholarly journals Elevated Expression of DecR1 Impairs ErbB2/Neu-Induced Mammary Tumor Development

2007 ◽  
Vol 27 (18) ◽  
pp. 6361-6371 ◽  
Author(s):  
Josie Ursini-Siegel ◽  
Ashish B. Rajput ◽  
Huiling Lu ◽  
Virginie Sanguin-Gendreau ◽  
Dongmei Zuo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Mammary Tumor ◽  
Fatty Acid Synthesis ◽  
Breast Cancer Cells ◽  
De Novo ◽  
Acid Synthesis ◽  
Mammary Tumor Cells

ABSTRACT Tumor cells utilize glucose as a primary energy source and require ongoing lipid biosynthesis for growth. Expression of DecR1, an auxiliary enzyme in the fatty acid β-oxidation pathway, is significantly diminished in numerous spontaneous mammary tumor models and in primary human breast cancer. Moreover, ectopic expression of DecR1 in ErbB2/Neu-induced mammary tumor cells is sufficient to reduce levels of ErbB2/Neu expression and impair mammary tumor outgrowth. This correlates with a decreased proliferative index and reduced rates of de novo fatty acid synthesis in DecR1-expressing breast cancer cells. Although DecR1 expression does not affect glucose uptake in ErbB2/Neu-transformed cells, sustained expression of DecR1 protects mammary tumor cells from apoptotic cell death following glucose withdrawal. Moreover, expression of catalytically impaired DecR1 mutants in Neu-transformed breast cancer cells restored Neu expression levels and increased mammary tumorigenesis in vivo. These results argue that DecR1 is sufficient to limit breast cancer cell proliferation through its ability to limit the extent of oncogene expression and reduce steady-state levels of de novo fatty acid synthesis. Furthermore, DecR1-mediated suppression of tumorigenesis can be uncoupled from its effects on Neu expression. Thus, while downregulation of Neu expression may contribute to DecR1-mediated tumor suppression in certain cell types, this is not an obligate event in all Neu-transformed breast cancer cells.

Sign in / Sign up

Export Citation Format

Share Document