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3. STAT1-deficient mice spontaneously develop estrogen receptor alpha-positive luminal mammary carcinomas

Author

Chan, Szeman, Vermi, William, Luo, Jingqin, Lucini, Laura, Rickert, Charles, Fowler, Amy M, Lonardi, Silvia, Arthur, Cora, Young, Larry JT, Levy, David E, Welch, Michael J, Cardiff, Robert D, and Schreiber, Robert D

Abstract

Abstract Introduction Although breast cancers expressing estrogen receptor-α (ERα) and progesterone receptors (PR) are the most common form of mammary malignancy in humans, it has been difficult to develop a suitable mouse model showing similar steroid hormone responsiveness. STAT transcription factors play critical roles in mammary gland tumorigenesis, but the precise role of STAT1 remains unclear. Herein, we show that a subset of human breast cancers display reduced STAT1 expression and that mice lacking STAT1 surprisingly develop ERα+/PR+ mammary tumors. Methods We used a combination of approaches, including histological examination, gene targeted mice, gene expression analysis, tumor transplantaion, and immunophenotyping, to pursue this study. Results Forty-five percent (37/83) of human ERα+ and 22% (17/78) of ERα- breast cancers display undetectable or low levels of STAT1 expression in neoplastic cells. In contrast, STAT1 expression is elevated in epithelial cells of normal breast tissues adjacent to the malignant lesions, suggesting that STAT1 is selectively downregulated in the tumor cells during tumor progression. Interestingly, the expression levels of STAT1 in the tumor-infiltrating stromal cells remain elevated, indicating that single-cell resolution analysis of STAT1 level in primary breast cancer biopsies is necessary for accurate assessment. Female mice lacking functional STAT1 spontaneously develop mammary adenocarcinomas that comprise > 90% ERα+/PR+ tumor cells, and depend on estrogen for tumor engraftment and progression. Phenotypic marker analyses demonstrate that STAT1-/- mammary tumors arise from luminal epithelial cells, but not myoepithelial cells. In addition, the molecular signature of the STAT1-/- mammary tumors overlaps closely to that of human luminal breast cancers. Finally, introduction of wildtype STAT1, but not a STAT1 mutant lacking the critical Tyr701 residue, into STAT1-/- mammary tumor cells results in apoptosis, demonstrating that the tumor suppressor function of STAT1 is cell-autonomous and requires its transcriptional activity. Conclusions Our findings demonstrate that STAT1 suppresses mammary tumor formation and its expression is frequently lost during breast cancer progression. Spontaneous mammary tumors that develop in STAT1-/- mice closely recapitulate the progression, ovarian hormone responsiveness, and molecular characteristics of human luminal breast cancer, the most common subtype of human breast neoplasms, and thus represent a valuable platform for testing novel treatments and detection modalities.

Published
2012

46. DFN Generator v2.0: A new tool to model the growth of large-scale natural fracture networks using fundamental geomechanics.

Author

Welch, Michael J., Lüthje, Mikael, and Oldfield, Simon J.

Subjects
*DIAPIRS, *FOLDS (Geology), *SALT domes, *GEOLOGICAL formations, *YOUNG'S modulus, *GEOLOGICAL modeling
Abstract

In this paper we present a new code to build geologically realistic models of natural fracture networks in geological formations, by simulating the processes of fracture nucleation, growth and interaction, based on geomechanical principles and the geological history of the formation. This code implements the fracture modelling algorithm described in Welch et al. (2020), developed to generate more accurate, better constrained models of large fracture networks than current stochastic techniques. It can efficiently build either implicit fracture models, explicit DFNs, or both, across large (km-scale) geological structures such as folds, major faults or salt diapirs. It will thus have applications in engineering and fluid flow modelling, including CO2 sequestration and geothermal energy, as well as in understanding the controls on the evolution of fracture networks. The code is written in C Sharp and is provided with two interfaces: a standalone interface with text file input and output, that can be compiled in standard C Sharp and can run simple models, and a plug-in interface for the Petrel geomodelling package from Schlumberger, that can run more complex models of real geological structures. The standalone version has been used to run extensive sensitivity analyses, which studied the influence of various mechanical and physical parameters (e.g. layer thickness, applied strain, Young's Modulus, etc.) on the fracture evolution and geometry, by varying the parameters individually in simple models. The Petrel plug-in has been used to evaluate the code applicability by running simulations of actual fractured layers in outcrops and in the subsurface, and comparing the results with observed fracture patterns. [ABSTRACT FROM AUTHOR]

Published
2022
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47. Systemic Exposure and Urinary Cortisol Effects of Fluticasone Propionate Formulated With Hydrofluoroalkane in 4- to 11-Year-Olds With Asthma

Author

Kim, Kenneth T., Milgrom, Henry, Kellie Yoon, Y., Levy, Arden L., Matz, Paul, Welch, Michael J., Cahn, Anthony, Collins, David A., Kathman, Steven, Mehta, Rashmi, Su, Sheng-Fang, and Kunka, Robert L.

Subjects
Chlorofluorocarbons -- Health aspects -- Research, Fluticasone -- Dosage and administration -- Research, Asthma -- Drug therapy -- Research, Health, Drug therapy, Research, Dosage and administration, Health aspects
Abstract

Keywords: Children; asthma; fluticasone; systemic effects; urinary cortisol 108 PediatricsSystemic Exposure and Urinary Cortisol Effects of Fluticasone Propionate Formulated With Hydrofluoroalkane in 4- to 11-Year-Olds With Asthma SAGE Publications, Inc.200810.1177/0091270007309704 [...]

Published
2008
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