Tissue Architecture and Microenvironment Sustain Hormone Signaling
Exposure to both prolactin and laminin-111 resulted in sustained activation of STAT5 and robust expression of milk proteins. The contributions of laminin-111 were shown to depend on the presence of dystroglycan. Understanding the complex factors that converge to regulate normal breast cell function should provide insights into how disruption of these processes may contribute to cancer.
Cells interact with their environments in part through protein receptors embedded in the cell membrane. Activation of a receptor by external signaling molecules sets off a complex chain of events within the cell that can result in alterations in protein structure and function and/or changes in gene expression. Proper integration of these signals is crucial for normal cell growth and development. A more complete understanding of these normal processes will help elucidate how aberrant signaling results in diseases such as cancer.
Barbara Vonderhaar, Ph.D., Chief of the Mammary Biology and Tumorigenesis Laboratory at CCR, studies prolactin, a hormone that interacts with prolactin receptor on the surface of breast epithelial cells and drives milk production during late pregnancy and lactation. There is evidence that prolactin signaling may be altered in breast cancer, but its contributions to this disease are not fully understood. Recently, Dr. Vonderhaar was involved in a study that helped clarify how prolactin induces milk protein production in mammary cells. The results, which were published in the Journal of Cell Biology, show that both the three-dimensional architecture of mammary cells and their interaction with their environment are critical modulators of prolactin signaling.
Although it has been shown that prolactin drives production of milk proteins in the mammary gland, most mammary cells grown in the laboratory fail to induce milk protein expression when treated with the hormone. Dr. Vonderhaar and colleagues discovered that this discrepancy is due to the fact that prolactin is unable to access its receptor when mammary cells are grown in a single layer on a cell culture plate.
To overcome this problem, mammary cells were grown in conditions that allow for the formation of three-dimensional structures that more closely resemble the native organization of the mammary gland. In this setting, prolactin was able to induce milk protein expression, but only in the presence of laminin-111. Laminin-111 is a protein located in the extracellular matrix, which is a collection of proteins and other molecules that provide structural support to cells. Laminin-111 and other proteins in the extracellular matrix can bind to receptors on the cell surface and influence cellular function.
The researchers found that prolactin was able to activate STAT5, the protein responsible for carrying the prolactin signal into the nucleus, in the absence of laminin-111; however, STAT5 activation was short-lived and expression of milk proteins was not observed. In contrast, exposure to both prolactin and laminin-111 resulted in sustained activation of STAT5 and robust expression of milk proteins. The contributions of laminin-111 were shown to depend on the presence of dystroglycan, a cell surface protein that interacts with laminins. Additional experiments revealed that sustained activation of STAT5 resulted in remodeling of specific regions of the DNA to a configuration that favors milk protein expression.
These studies show that three-dimensional tissue architecture and interaction with the extracellular matrix are crucial modulators of cellular response to environmental signals. Elucidation of the complex factors that converge to regulate normal cell function should provide insight into how disruption of these processes may contribute to diseases such as cancer.Summary Posted: Thu, 01/01/2009
J Cell Biol. 2009 Jan 12;184(1):57-66 PubMed Link