Dissection of Signaling Events in the Mammary Gland in Vivo

Institution: The Burnham Institute for Medical Research
Investigator(s): Yuehai Ke, Ph.D. -
Award Cycle: 2003 (Cycle IX) Grant #: 9FB-0170 Award: $86,400
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Biology of the Normal Breast: the starting point

Initial Award Abstract (2003)
Cells respond to changes in the physical and chemical properties of the environment. These cues control many aspects of cell function including migration, proliferation, differentiation and death. Many different pathways cooperate and participate in these processes and the disruption of one of them could easily lead to cellular disorders, such as the malignant cell growth in breast cancer patients. Moreover, some of these pathways are found systematically activated in breast cancer. Before finding the best way to cure this kind of tumor, we need to understand how these pathways work under a normal physiological condition and identify the key proteins involved in these processes. A large number of proteins with different functions are involved in these pathways. During this work, I will focus on a particular class of proteins called tyrosine phosphatases. These proteins may function in positive or negative fashion in normal breast development and also in procession of breast cancers. I will elucidate these functions in a new mouse model system that was created in our laboratory.

A crucial question in cancer biology is how some proteins are activated the others inactivated in tumors. A good way to answer this elegant question is to dissect step by step the different pathways leading to the transduction of an extracellular signal from the cell surface to specific intracellular sites. Tyrosine phophatases are believed to play important roles but little is known about their functions in health and disease. My project will be centered on understanding the biological function of a cytoplasmic tyrosine phosphatase Shp-2 in the mammary gland in mice.

Thanks to the rapid development of molecular biology, we are now able to assess the involvement of a specific gene in a specific tissue in vivo using the conditional mouse gene knockout technology. Our laboratory has had great success in creating mouse models using this technique, which will allow me to determine the physiological function of Shp-2 tyrosine phosphatase in mammary gland development.

Due to the generation of this novel mouse model in or laboratory, we have the unprecedented opportunity to dissect the molecular mechanism for the control of normal breast development and ultimately the molecular basis for the pathogenesis of breast cancer.

Final Report (2005)
Tyrosine phosphatase, Shp2 and its associate protein Gab2 are believed to play important roles in cell proliferation, differentiation and death. Some pathways cooperate and participate in these basic processes and disruption of one of them could lead to a defect in breast development or even cause cancer.

The first aim of this work was to determine the physiological function of Shp2 in mammary gland development, we created a line of mice in which the shp2 gene is specifically knocked-out in mammary gland. We show that mice lacking Shp2 have impaired mammary gland development and reduced milk secretion. Further biochemistry studies suggested that Shp2 bi-directionally modulates Stat5 and Stat3 activities which are the most important regulators in milk production and involution (return of the mammary gland to the pre-lactation state). This work is the first to provide novel insight into the complex mechanisms for regulation of various Stat family members. Elucidating the biological functions of Shp2 will lead to a better understanding basic mechanism controlling breast development and cancer progression.

The second objective of this project was to characterize role of Gab2 in breast cancer progression. As an important docking protein that recruits Shp2, Gab2 (Grb2-associated binder 2) has been recently reported to be markedly overexpressed in various human breast cancer cell lines, suggesting Gab2 might be a critical modulator for breast cancer. We bred Gab2-deficient tumor-prone mice by crossing Gab2-null mice with transgenic mice carrying MMTV/Neu (which induces mammary tumor rapidly), we found that the absence of Gab2 fails to prevent generation of mammary tumors but alleviates metastatic lesions by suppressing Erk activity which is a critical molecule in tumor outgrowth and metastasis. This is first in vivo evidence to elucidate Gab2 physiological role in breast cancer which defines a potential therapeutic target for breast cancer metastasis.