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Schmeichel, Karen L.; Weaver, Valerie M.; Bissell, Mina J.

doi:10.1023/a:1018751124382

Cited by 79 publications

(26 citation statements)

References 78 publications

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“…2 A ; experimental schema), which better mimics physiological growth conditions than 2D cultures (8, 30–32), malignant breast cancer T4-2 cells showed higher levels of total and phospho (T788/789) β1-integrins compared to its counterpart non-malignant S1 cells (Fig. 2 B ).…”

Section: Resultsmentioning

confidence: 99%

NF-κB Regulates Radioresistance Mediated By β1-Integrin in Three-Dimensional Culture of Breast Cancer Cells

2013

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β1-integrin induction enhances breast cancer cell survival after exposure to ionizing radiation (IR), but the mechanisms of this effect remain unclear. Although NF-κB initiates prosurvival signaling pathways post-IR, the molecular function of NF-κB with other key elements in radioresistance, particularly with respect to extracellular matrix-induced signaling, is not known. We discovered a typical NF-κB binding site in the β1-integrin promoter region, indicating a possible regulatory role for NF-κB. Using 3-dimensional laminin-rich extracellular matrix (3D lrECM) culture, we show that NF-κB is required for β1-integrin transactivation in T4-2 breast cancer cells post-IR. Inhibition of NF-κB reduced clonogenic survival, and induced apoptosis and cytostasis in formed tumor colonies. In addition, T4-2 tumors with inhibition of NF-κB activity exhibit decreased growth in athymic mice, which was further reduced by IR with downregulated β1-integrin expression. Direct interactions between β1-integrin and NF-κB p65 were induced in non-malignant breast epithelial cells, but not in malignant cells, indicating context specific regulation. Since β1-integrin also activates NF-κB, our findings reveal a novel forward feedback pathway that could be targeted to enhance therapy.

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Section: Resultsmentioning

confidence: 99%

NF-κB Regulates Radioresistance Mediated By β1-Integrin in Three-Dimensional Culture of Breast Cancer Cells

2013

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“…Such studies identified specific ECM protein-integrin interactions, matrix stiffness, and matrix architecture as critical mediators of tumor cell function (15–18). Single ECM molecules, including collagen I, fibronectin, and tenascin-C, display clear roles in promoting tumor cell proliferation, motility, and invasion (18–22).…”

Section: Introductionmentioning

confidence: 99%

Quantitative extracellular matrix proteomics to study mammary and liver tissue microenvironments

Goddard

Hill

Barrett

et al. 2016

The International Journal of Biochemistry & Cell Biology

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Normal epithelium exists within a dynamic extracellular matrix (ECM) that is tuned to regulate tissue specific epithelial cell function. As such, ECM contributes to tissue homeostasis, differentiation, and disease, including cancer. Though it is now recognized that the functional unit of normal and transformed epithelium is the epithelial cell and its adjacent ECM, we lack a basic understanding of tissue-specific ECM composition and abundance, as well as how physiologic changes in ECM impact cancer risk and outcomes. While traditional proteomic techniques have advanced to robustly identify ECM proteins within tissues, methods to determine absolute abundance have lagged. Here, with a focus on tissues relevant to breast cancer, we utilize mass spectrometry methods optimized for absolute quantitative ECM analysis. Employing an extensive protein extraction and digestion method, combined with stable isotope labeled Quantitative conCATamer (QconCAT) peptides that serve as internal standards for absolute quantification of protein, we quantify 98 ECM, ECM-associated, and cellular proteins in a single analytical run. In rodent models, we applied this approach to the primary site of breast cancer, the normal mammary gland, as well as a common and particularly deadly site of breast cancer metastasis, the liver. We find that mammary gland and liver have distinct ECM abundance and relative composition. Further, we show mammary gland ECM abundance and relative compositions differ across the reproductive cycle, with the most dramatic changes occurring during the pro-tumorigenic window of weaning-induced involution. Combined, this work suggests ECM candidates for investigation of breast cancer progression and metastasis, particularly in postpartum breast cancers that are characterized by high metastatic rates. Finally, we suggest that with use of absolute quantitative ECM proteomics to characterize tissues of interest, it will be possible to reconstruct more relevant in vitro models to investigate tumor-ECM dynamics at higher resolution.

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“…The importance of adipose tissue interactions with normal, nontransformed mammary epithelial cells in promoting growth and development of spherical, ductlike organized structures is well established phenomenologically (Schmeichel et al, 1998). Many groups have shown that mammary ducts do not form properly without the appropriate interactions with adipose tissue and have identified various signaling mechanisms involved in this process (Howlett and Bissell, 1993;Zangani et al, 1999;Huss and Kratz, 2001).…”

Section: Introductionmentioning

confidence: 99%

Adipocyte-secreted factors synergistically promote mammary tumorigenesis through induction of anti-apoptotic transcriptional programs and proto-oncogene stabilization

et al. 2003

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Mammary epithelial cells are embedded in a unique extracellular environment to which adipocytes and other stromal cells contribute. Mammary epithelial cells are critically dependent on this milieu for survival. However, it remains unknown which adipocyte-secreted factors are required for the survival of the mammary epithelia and what role these adipokines play in the process of ductal carcinoma tumorigenesis. Here, we take a systematic molecular approach to investigate the multiple ways adipocytes and adipokines can uniquely influence the characteristics and phenotypic behavior of malignant breast ductal epithelial cells. Microarray analysis and luciferase reporter assays indicate that adipokines specifically induce several transcriptional programs involved in promoting tumorigenesis, including increased cell proliferation (IGF2, FOS, JUN, cyclin D1), invasive potential (MMP1, ATF3), survival (A20, NFjB), and angiogenesis. One of the key changes in the transformed ductal epithelial cells associated with the cell cycle involves the induction of NFjB (five-fold) and cyclin D1 (three-fold). We show that by regulating the transcription of these molecules, the synergistic activity of adipocyte-derived factors can potentiate MCF-7 cell proliferation. Furthermore, compared to other stromal cell-secreted factors, the full complement of adipokines shows an unparalleled ability to promote increased cell motility, migration, and the capacity for angiogenesis. Adipocyte-secreted factors can affect tumorigenesis by increasing the stabilization of pro-oncogenic factors such as b-catenin and CDK6 as a result of a reduction in the gene expression of their inhibitors (i.e. p18). An in vivo coinjection system using 3T3-L1 adipocytes and SUM159PT cells effectively recapitulates the host-tumor interactions in primary tumors. Type VI collagen, a soluble extracellular matrix protein abundantly expressed in adipocytes, is further upregulated in adipocytes during tumorigenesis. It promotes GSK3b phosphorylation, b-catenin stabilization, and increased b-catenin activity in breast cancer cells and may critically contribute towards tumorigenesis when not counterbalanced by other factors.

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Untitled

Cited by 79 publications

References 78 publications

NF-κB Regulates Radioresistance Mediated By β1-Integrin in Three-Dimensional Culture of Breast Cancer Cells

NF-κB Regulates Radioresistance Mediated By β1-Integrin in Three-Dimensional Culture of Breast Cancer Cells

Quantitative extracellular matrix proteomics to study mammary and liver tissue microenvironments

Adipocyte-secreted factors synergistically promote mammary tumorigenesis through induction of anti-apoptotic transcriptional programs and proto-oncogene stabilization

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