scholarly journals Time-lapse Imaging of Primary Preneoplastic Mammary Epithelial Cells Derived from Genetically Engineered Mouse Models of Breast Cancer

10.3791/50198 ◽  
2013 ◽  
Author(s):  
Rebecca E. Nakles ◽  
Sarah L. Millman ◽  
M. Carla Cabrera ◽  
Peter Johnson ◽  
Susette Mueller ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epithelial Cells ◽  
Mouse Models ◽  
Mammary Epithelial Cells ◽  
Time Lapse ◽  
Genetically Engineered ◽  
Mammary Epithelial ◽  
Genetically Engineered Mouse Models ◽  
Time Lapse Imaging

scholarly journals The ETS Transcription Factor ESE-1 Transforms MCF-12A Human Mammary Epithelial Cells via a Novel Cytoplasmic Mechanism

2004 ◽  
Vol 24 (12) ◽  
pp. 5548-5564 ◽  
Author(s):  
Jason D. Prescott ◽  
Karen S. N. Koto ◽  
Meenakshi Singh ◽  
Arthur Gutierrez-Hartmann
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Epithelial Cells ◽  
Nuclear Localization ◽  
Human Breast Cancer ◽  
Mammary Epithelial Cells ◽  
Cell Transformation ◽  
Mammary Epithelial ◽  
Human Breast ◽  
Human Mammary Epithelial

ABSTRACT Several different transcription factors, including estrogen receptor, progesterone receptor, and ETS family members, have been implicated in human breast cancer, indicating that transcription factor-induced alterations in gene expression underlie mammary cell transformation. ESE-1 is an epithelium-specific ETS transcription factor that contains two distinguishing domains, a serine- and aspartic acid-rich (SAR) domain and an AT hook domain. ESE-1 is abundantly expressed in human breast cancer and trans-activates epithelium-specific gene promoters in transient transfection assays. While it has been presumed that ETS factors transform mammary epithelial cells via their nuclear transcriptional functions, here we show (i) that ESE-1 protein is cytoplasmic in human breast cancer cells; (ii) that stably expressed green fluorescent protein-ESE-1 transforms MCF-12A human mammary epithelial cells; and (iii) that the ESE-1 SAR domain, acting in the cytoplasm, is necessary and sufficient to mediate this transformation. Deletion of transcriptional regulatory or nuclear localization domains does not impair ESE-1-mediated transformation, whereas fusing the simian virus 40 T-antigen nuclear localization signal to various ESE-1 constructs, including the SAR domain alone, inhibits their transforming capacity. Finally, we show that the nuclear localization of ESE-1 protein induces apoptosis in nontransformed mammary epithelial cells via a transcription-dependent mechanism. Together, our studies reveal two distinct ESE-1 functions, apoptosis and transformation, where the ESE-1 transcription activation domain contributes to apoptosis and the SAR domain mediates transformation via a novel nonnuclear, nontranscriptional mechanism. These studies not only describe a unique ETS factor transformation mechanism but also establish a new paradigm for cell transformation in general.

scholarly journals The H1047R PIK3CA oncogene induces a senescence-like state, pleiotropy and acute HSP90 dependency in HER2+ mammary epithelial cells

2019 ◽  
Vol 40 (10) ◽  
pp. 1179-1190 ◽  
Author(s):  
Anindita Chakrabarty ◽  
Sreeraj Surendran ◽  
Neil E Bhola ◽  
Vishnu S Mishra ◽  
Tasaduq Hussain Wani ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Mammary Epithelial Cells ◽  
Breast Tumors ◽  
Genetically Engineered ◽  
Mammary Epithelial ◽  
Hsp90 Inhibition ◽  
Mesenchymal Transition ◽  
Pik3ca Mutations

Abstract In pre-clinical models, co-existence of Human Epidermal Growth Factor Receptor-2 (HER2)-amplification and PI3K catalytic subunit (PIK3CA) mutations results in aggressive, anti-HER2 therapy-resistant breast tumors. This is not always reflected in clinical setting. We speculated that the complex interaction between the HER2 and PIK3CA oncogenes is responsible for such inconsistency. We performed series of biochemical, molecular and cellular assays on genetically engineered isogenic mammary epithelial cell lines and breast cancer cells expressing both oncogenes. In vitro observations were validated in xenografts models. We showed that H1047R, one of the most common PIK3CA mutations, is responsible for endowing a senescence-like state in mammary epithelial cells overexpressing HER2. Instead of imposing a permanent growth arrest characteristic of oncogene-induced senescence, the proteome secreted by the mutant cells promotes stem cell enrichment, angiogenesis, epithelial-to-mesenchymal transition, altered immune surveillance and acute vulnerability toward HSP90 inhibition. We inferred that the pleiotropism, as observed here, conferred by the mutated oncogene, depending on the host microenvironment, contributes to conflicting pre-clinical and clinical characteristics of HER2+, mutated PIK3CA-bearing tumor cells. We also came up with a plausible model for evolution of breast tumors from mammary epithelial cells harboring these two molecular lesions.

scholarly journals Ductal tree ablation by local delivery of ethanol prevents tumor formation in an aggressive mouse model of breast cancer

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Elizabeth Kenyon ◽  
Jennifer J. Westerhuis ◽  
Maximilian Volk ◽  
Jeremy Hix ◽  
Shatadru Chakravarty ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Prophylactic Mastectomy ◽  
Treated Group ◽  
Tumor Formation ◽  
Mammary Epithelial ◽  
Tumor Incidence ◽  
Control Group ◽  
Untreated Control Group

Abstract Background Prophylactic mastectomy is the most effective intervention to prevent breast cancer. However, this major surgery has life-changing consequences at the physical, emotional, psychological, and social levels. Therefore, only high-risk individuals consider this aggressive procedure, which completely removes the mammary epithelial cells from which breast cancer arises along with surrounding tissue. Here, we seek to develop a minimally invasive procedure as an alternative to prophylactic mastectomy by intraductal (ID) delivery of a cell-killing solution that locally ablates the mammary epithelial cells before they become malignant. Methods After ID injection of a 70% ethanol-containing solution in FVB/NJ female animals, ex vivo dual stained whole-mount tissue analysis and in vivo X-ray microcomputed tomography imaging were used to visualize ductal tree filling, and histological and multiplex immunohistochemical assays were used to characterize ablative effects and quantitate the number of intact epithelial cells and stroma. After ID injection of 70% ethanol or other solutions in cancer-prone FVB-Tg-C3(1)-TAg female animals, mammary glands were palpated weekly to establish tumor latency and examined after necropsy to record tumor incidence. Statistical difference in median tumor latency and tumor incidence between experimental groups was analyzed by log-rank test and logistic mixed-effects model, respectively. Results We report that ID injection of 70% ethanol effectively ablates the mammary epithelia with limited collateral damage to surrounding stroma and vasculature in the murine ductal tree. ID injection of 70% ethanol into the mammary glands of the C3(1)-TAg multifocal breast cancer model significantly delayed tumor formation (median latency of 150 days in the untreated control group [n = 25] vs. 217 days in the ethanol-treated group [n = 13], p value < 0.0001) and reduced tumor incidence (34% of glands with tumors [85 of 250] in the untreated control group vs. 7.3% of glands with tumor [7 of 95] in the ethanol-treated group, risk ratio = 4.76 [95% CI 1.89 to 11.97, p value < 0.0001]). Conclusions This preclinical study demonstrates the feasibility of local ductal tree ablation as a novel strategy for primary prevention of breast cancer. Given the existing clinical uses of ethanol, ethanol-based ablation protocols could be readily implemented in first-in-human clinical trials for high-risk individuals.

scholarly journals Microarray analysis of RhoC-transformed mammary epithelial cells suggests molecular mechanisms of inflammatory breast cancer

10.1038/87212 ◽  
2001 ◽  
Vol 27 (S4) ◽  
pp. 73-73
Author(s):  
Sofia Merajver ◽  
Zhi-Fen Wu ◽  
Tammy Chang ◽  
Hamid Mirshahidi ◽  
Paul Meltzer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epithelial Cells ◽  
Microarray Analysis ◽  
Inflammatory Breast Cancer ◽  
Molecular Mechanisms ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial
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