Progress 10/01/06 to 09/30/07
Outputs
OUTPUTS: The goal of this project is to understand the ways and mechanisms in which intracellular signaling mechanisms occur inside epithelial cells within the normal mammary gland. These epithelial cells respond to hormonal signals during their growth and when they are synthesizing and secreting milk. Two of these critical hormones are the pituitary hormone, prolactin and the ovarian hormone, progesterone. While each of these hormones has established individual roles, our work has identified that these two hormones also work cooperatively and synergistically on mammary epithelial cells to induce specific and unique signaling events. In particular, we have identified a unique transcription factor binding site that coordinates the activation of receptors for these hormones. We found that this site is an enhancer region that induces transcription from downstream genes. We also found that the site is activated by upstream signaling molecules that include Src, Fyn and Jak2, while other
molecules such as Bcl6 may also participate in its activation. We have presented these results at various scientific venues and are preparing the work for publication in a peer-reviewed journal. Our ongoing goal is to identify the factor(s) that are recruited to this site and to establish in which cells this site is activated. This work has also provided critical preliminary data for several grant submissions to federal agencies to extend and continue this work as relevant to the disease of breast cancer.
PARTICIPANTS: Russell C. Hovey, PhD; PI. Experimentation, data analysis, project oversight and coordination. Josephine F. Trott, PhD; co-PI. Experimentation and data analysis Joseph Morabito, graduate student. Experimentation and data analysis. Heather Fairfield, undergraduate student. Experimentation and data analysis.
TARGET AUDIENCES: This work has been presented as poster presentations to graduate student forums and to audiences interested in animal science and breast cancer. The work has also provided a basis for graduate and undergraduate research efforts.
PROJECT MODIFICATIONS: none
Impacts
This work is important to understanding how hormones work cooperatively during mammary gland function as occurs both during heifer growth and during milk production during lactation. Hence this work is extremely important for understanding the biological basis for dairy production. By understanding the biological function of this genetic enhancer region we will then be able to determine which genes are regulated by these two hormones working together. While this work is very basic in nature and will first be used to understand molecular and cellular mechanisms, it ultimately will be useful for genetic selection and modification efforts. The work also has direct application to understanding the basis for breast cancer as these hormones are also critical regulators of cell function in the disease. Hence the work has broad application for dairy producers and breast cancer patients alike.
Publications
- Satoh K, Hovey RC, Malewski T, Warri A, Goldhar AS, Ginsburg E, Saito K, Lydon JP, Vonderhaar BK. Progesterone enhances branching morphogenesis in the mouse mammary gland by increased expression of Msx2. Oncogene. 2007 epub ahead of print.
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Progress 10/01/05 to 09/30/07
Outputs
OUTPUTS: This research has terminated. PARTICIPANTS: Not relevant to this project. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
This research has terminated.
Publications
- No publications reported this period
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Progress 10/01/05 to 09/30/06
Outputs
The objective of this work is to understand the molecular and biochemical mechanism by which the hormones progesterone and prolactin activate cells within the mammary glands. It is well-established that these two hormones are important for normal mammary gland growth as well as milk production, yet their cooperative effects are unclear. To this end we have been investigating how the two hormones work together on a target gene promoter in mammary epithelial cells. Our work has led to the identification of a unique transcription factor complex in normal mammary epithelial cells that we have termed mammary gland specific factor. Using this model we have been able to determine the signaling pathway that regulates the activation of mammary gland specific factor by the two hormones and has led us to propose a novel mechanism of transcription activation in cells from the mammary glands. In our attempt to establish the nature of the transcription-regulating complex we have
adopted a candidate approach whereby we used various competitor oligonucleotides to compete for the complex in vitro. Using this approach we have identified key candidate transcription factors that appear to participate in this transcriptional response to the two hormones. These data will help us to further dissect the signaling pathway(s) and factors involved in the unique response by mammary cells to these two hormones.
Impacts
The hormones progesterone and prolactin have both been implicated in the regulation of mammary gland growth, milk production and breast cancer. What is not known, however, is how the two hormones act together on the target mammary epithelial cell population. To this end we are determining the intracellular mechanisms responsible for this combined hormone action. Ultimately these basic studies will increase the opportunity for hormonal modulation of mammary gland growth and lactation potential, as well as help resolve whether this signaling pathway and mechanism is a future target for breast cancer therapies.
Publications
- No publications reported this period
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