Biological Responses to TGF-β in the Mammary Epithelium Show a Complex Dependency on Smad3 Gene Dosage with Important Implications for Tumor Progression

Kohn, Ethan A.; Yang, Yuan; Du, Zhifeng; Nagano, Yukiko; Schyndle, Catherine M.H. Van; Herrmann, Michelle A.; Heldman, Madeleine R.; Chen, Jin‐Qiu; Stuelten, Christina H.; Flanders, Kathleen C.; Wakefield, Lalage M.

doi:10.1158/1541-7786.mcr-12-0136-t

Cited by 21 publications

(17 citation statements)

References 23 publications

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“…NUR77 NUR77 (NR4A1) expression is elevated in both ER+ and ER− breast tumors (Muscat et al 2013), and NUR77 expression is correlated with decreased relapsefree survival in breast cancer (Alexopoulou et al 2010), consistent with reports of its pro-oncogenic role in breast cancer (Hedrick et al 2015). Contradictory to a previous report of NUR77 having anti-migratory effects in MCF-10A breast cancer cells, recently, NUR77 expression was shown to have pro-migratory effects through activation of TGF-beta signaling (Zhou et al 2014), which is known to have an important role in breast cancer metastasis (Moore et al 2008, Kohn et al 2012, Luwor et al 2015.…”

Section: Estrogen-relatedsupporting

confidence: 81%

Emerging functional roles of nuclear receptors in breast cancer

Doan

Graham

2017

Journal of Molecular Endocrinology

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Nuclear receptors (NRs) have been targets of intensive drug development for decades due to their roles as key regulators of multiple developmental, physiological and disease processes. In breast cancer, expression of the estrogen and progesterone receptor remains clinically important in predicting prognosis and determining therapeutic strategies. More recently, there is growing evidence supporting the involvement of multiple nuclear receptors other than the estrogen and progesterone receptors, in the regulation of various processes important to the initiation and progression of breast cancer. We review new insights into the mechanisms of action of NRs made possible by recent advances in genomic technologies and focus on the emerging functional roles of NRs in breast cancer biology, including their involvement in circadian regulation, metabolic reprogramming and breast cancer migration and metastasis.

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Section: Estrogen-relatedsupporting

confidence: 81%

Emerging functional roles of nuclear receptors in breast cancer

Doan

Graham

2017

Journal of Molecular Endocrinology

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“…Most histologic studies of age-related involution have focused on understanding changes in epithelium(9, 14-17). Our results confirm dramatic epithelial changes in epithelial nuclear density with aging, but also illustrate that aging produces important changes in all the histological components of breast(10, 18-21).…”

Section: Discussionmentioning

confidence: 99%

Digital histologic analysis reveals morphometric patterns of age-related involution in breast epithelium and stroma

Sandhu¹,

Chollet‐Hinton

Kirk

et al. 2016

Human Pathology

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Complete age-related regression of mammary epithelium, often termed post-menopausal involution, is associated with decreased breast cancer risk. However, most studies have qualitatively assessed involution. We quantitatively analyzed epithelium, stroma, and adipose tissue from histologically normal breast tissue of 454 patients in the Normal Breast Study (NBS). High-resolution digital images of normal breast Hematoxylin & Eosin stained slides were partitioned into epithelium, adipose tissue, and non-fatty stroma. Percentage area and nuclei per unit area (nuclear density) were calculated for each component. Quantitative data were evaluated in association with age using linear regression and cubic spline models Stromal area decreased (p=0.0002) and adipose tissue area increased (p<0.0001), with an approximate 0.7% change in area for each component, until age 55 when these area measures reached a steady state. While epithelial area did not show linear changes with age, epithelial nuclear density decreased linearly beginning in the third decade of life. No significant age-related trends were observed for stromal or adipose nuclear density. Digital image analysis offers a high-throughput method for quantitatively measuring tissue morphometry and for objectively assessing age-related changes in adipose tissue, stroma, and epithelium. Epithelial nuclear density is a quantitative measure of age-related breast involution that begins to decline in the early premenopausal period.

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“…Automation allows more accurate and reproducible assessment of protein levels compared with traditional Western blots (Chen et al, 2013). Samples were analyzed as previously described unless stated otherwise (Kohn et al, 2012). In brief, samples containing the same amount of protein, 57 ng (mouse) or 20 ng (human) for ABCG2 analysis and 20 ng (human and mouse) for P-gp analysis, were used.…”

Section: Methodsmentioning

confidence: 99%

Overlapping Substrate and Inhibitor Specificity of Human and Murine ABCG2

Bakhsheshian¹,

Hall²,

Robey³

et al. 2013

Drug Metab Dispos

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ABCG2 (also known as breast cancer resistance protein) is an ATP-binding cassette (ABC) transporter localized to the plasma membrane where it mediates the efflux of xenobiotics, including potential therapeutics. Studies investigating Abcg2 function at the blood-brain barrier in mouse models are often compared with human ABCG2 function. It is critical to understand the nature of species differences between mouse and human ABCG2, since extrapolations are made from murine data to humans. Two independent drug-selected cell line pairs expressing human or mouse ABCG2 were compared for efflux of fluorescent substrates using flow cytometry. To this end, we developed and characterized a new mouse Abcg2-expressing subline that demonstrated efflux of known fluorescent ABCG2 substrates and increased resistance to mitoxantrone, which is reduced in the presence of the ABCG2 inhibitor Ko143. Our results indicate that the substrate specificity of human and mouse ABCG2 is very similar. We identified a new human and mouse ABCG2 substrate, a porphyrin analog, purpurin-18 (Pp-18), which is not a substrate for P-glycoprotein or multidrug resistance protein 1. The ability of inhibitors to block efflux activity of ABCG2 was assessed using Pp-18. Inhibitors also demonstrated similar effects on human and mouse ABCG2. Chrysin, benzoflavone, and cyclosporin A inhibited Pp-18 efflux in both human and mouse ABCG2. The similarity of the substrate and inhibitor specificity of human and mouse ABCG2 supports interpretation of mouse models in understanding the clinical, pharmacological, and physiologic roles of ABCG2.

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Biological Responses to TGF-β in the Mammary Epithelium Show a Complex Dependency on Smad3 Gene Dosage with Important Implications for Tumor Progression

Cited by 21 publications

References 23 publications

Emerging functional roles of nuclear receptors in breast cancer

Emerging functional roles of nuclear receptors in breast cancer

Digital histologic analysis reveals morphometric patterns of age-related involution in breast epithelium and stroma

Overlapping Substrate and Inhibitor Specificity of Human and Murine ABCG2

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