scholarly journals The importance of the microenvironment in breast cancer progression: recapitulation of mammary tumorigenesis using a unique human mammary epithelial cell model and a three-dimensional culture assay

1996 ◽  
Vol 74 (6) ◽  
pp. 833-851 ◽  
Author(s):  
V. M. Weaver ◽  
M. J. Bissell ◽  
A. H. Fischer ◽  
O. W. Peterson
Keyword(s):  
Breast Cancer ◽  
Extracellular Matrix ◽  
Epithelial Cells ◽  
Adhesion Molecules ◽  
Three Dimensional ◽  
Mammary Epithelial ◽  
Tissue Structure ◽  
Human Mammary Epithelial

The extracellular matrix (ECM) is a dominant regulator of tissue development and homeostasis. "Designer microenvironments" in culture and in vivo model systems have shown that the ECM regulates growth, differentiation, and apoptosis in murine and human mammary epithelial cells (MEC) through a hierarchy of transcriptional events involving the intricate interplay between soluble and physical signaling pathways. Furthermore, these studies have shown that these pathways direct and in turn are influenced by the tissue structure. Tissue structure is directed by the cooperative interactions of the cell–cell and cell–ECM pathways and can be modified by stromal factors. Not surprisingly then, loss of tissue structure and alterations in ECM components are associated with the appearance and dissemination of breast tumors, and malignancy is associated with perturbations in cell adhesion, changes in adhesion molecules, and a stromal reaction. Several lines of evidence now support the contention that the pathogenesis of breast cancer is determined (at least in part) by the dynamic interplay between the ductal epithelial cells, the microenvironment, and the tissue structure (acini). Thus, to understand the mechanisms involved in carcinogenesis, the role of the microenvironment (ECM as well as the stromal cells) with respect to tissue structure should be considered and studied. Towards this goal, we have established a unique human MEC model of tumorigenesis, which in concert with a three-dimensional assay, recapitulates many of the genetic and morphological changes observed in breast cancer in vivo. We are currently using this system to understand the role of the microenvironment and tissue structure in breast cancer progression.Key words: extracellular matrix, integrin, adhesion molecules, breast cancer, microenvironment.

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.

Effect of the extracellular matrix on plasminogen activator isozyme activities of human mammary epithelial cells in culture

1983 ◽  
Vol 3 (6) ◽  
pp. 982-990
Author(s):  
N S Yang ◽  
C Park ◽  
C Longley ◽  
P Furmanski
Keyword(s):  
Extracellular Matrix ◽  
Epithelial Cells ◽  
Plasminogen Activator ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Collagen Gels ◽  
Human Mammary Epithelial Cells ◽  
Human Mammary Epithelial ◽  
Normal Human ◽  
Mcf 7

Multiple molecular forms of plasminogen activator were detected in normal human mammary epithelial cells in culture. Cells derived from (normal) breast mammoplasty specimens and grown on the surface of collagen gels exhibited three major classes of plasminogen activator isozymes (Mr = 100,000 [100K], 75,000 [75K], and 55,000 [55K]). The activity of the 100K and 75K isozymes was greatly reduced when the cells were grown on conventional tissue-culture-grade plastic surfaces. MCF-7, a human mammary carcinoma cell line, exhibited predominantly or exclusively the 55K isozyme, irrespective of the cell growth substratum. The activity of the 55K isozyme was more than twofold higher for MCF-7 cells grown on collagen gels than for cells grown on plastic. Progesterone, diethylstilbestrol, and estrogen stimulated the activity of the 55K isozyme of MCF-7 cells, but only when the cells were grown on a plastic surface. The plasminogen activator activities of the normal human mammary epithelial cells were not stimulated by these hormones, irrespective of the growth substratum. These results show that the expression of plasminogen activator isozymes by human mammary epithelial cells is subject to modulation by the extracellular matrix. Normal and malignant cells may differ in their responsiveness to these effects.

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