Molecular Structure of BAG-1:a New Protein in Breast Cancer

Institution: The Burnham Institute for Medical Research
Investigator(s): Kathryn Ely, Ph.D. -
Award Cycle: 1999 (Cycle V) Grant #: 5JB-0065 Award: $291,778
Award Type: IDEAS II
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (1999)
Like normal breast tissues, many breast tumors depend on estrogens for growth and differentiation. Because of this, for the past three decades, endocrine therapies based on antiestrogens have been widely used to treat breast cancer. This treatment is often effective for patients, but with time the tumors become unresponsive to tamoxifen and the treatment fails. New approaches are needed that don't rely solely on antiestrogens. The focus of this project is BAG-1, a new protein that is linked to the estrogen receptor and makes breast cancer cells resistant to the growth inhibitory effects of tamoxifen. Breast cancer cells continue to grow and divide in the presence of tamoxifen, if BAG-1 is present. The goal of the present study is to generate a molecular image of BAG-1 using the methods of x-ray crystallography and nuclear magnetic resonance (NMR) imaging.

Our aims are to study a conserved domain of BAG-1 by NMR to gain information on functional properties that might prove useful in future drug design efforts. Previous work by our collaborators has served to isolate BAG-1, develop antibodies for purification and analysis, and understand the mechanism of its cellular functions. To this point, we have been able to produce BAG-1 as either the entire protein or the functional regions, and purify them in preparation for crystallization. A key long-term goal is to study BAG-1ís interaction with another protein, celled Hsp70, which is a key link to hormone responsiveness. It is clear that BAG-1 is associated with hormone responsiveness, but the required structural features and how the smaller protein domains and accessory proteins, such as Hsp70, interact is unclear. The structure will reveal the precise 3-dimensional features of BAG-1 and will provide critical clues linking structure and function.

These pilot studies could serve as the first step in a drug discovery process for an alternate treatment of breast cancer. The molecular models may offer a new perspective to search for therapies for breast cancer. Since BAG-1 may contribute to treatment failure with tamoxifen or other antiestrogens, the BAG-1 molecule itself may represent a novel target for an entirely new treatment strategy.


Final Report (2001)
Like normal breast tissues, breast tumors depend on estrogens for growth and differentiation. Because of this, for the past three decades, endocrine therapies based on anti estrogens have been widely used to treat breast cancer. This treatment is often effective for patients, but with time the tumors become unresponsive to tamoxifen, for example, and the treatment fails. New approaches are needed that don't rely solely on anti estrogens. The focus of this project is BAG1, a new protein that is linked to the estrogen receptor and makes breast cancer cells resistant to the growth inhibitory effects of tamoxifen.

The level of BAG1 is elevated in breast cancers. BAG1 promotes tumor growth and metastatic spread, and renders breast tumors resistant to anti cancer drugs such as tamoxifen. BAG1 and other members of the BAG family share a conserved sequence located in the carboxyl terminal portion of the proteins. This conserved segment, called the 'BAG domain' binds to the molecular chaperone Hsp70 and therefore is functionally important to our studies. To understand the role of BAG1 as a regulator of Hsp70 and the effect of these protein interactions in breast cancer, our goal in this project was to generate a molecular image of BAG 1 using nuclear magnetic resonance (NMR) imaging. Multidimensional NMR analyses revealed that the protein is a helical bundle and the structure was used along with mutagenesis to define the contact interfaces between BAG1 and the chaperone molecule. These contacts may be associated with the effect of BAG1 on tumor growth and metastasis.

These pilot studies could serve as the first step in a drug discovery process for an alternate treatment of breast cancer. The molecular models may offer a new perspective to search for therapies for breast cancer. Since BAG-1 may contribute to treatment failure with tamoxifen or other antiestrogens, the BAG-1 molecule itself may represent a novel target for an entirely new treatment strategy.

Structural analysis of BAG1 cochaperone and its interactions with Hsc70 heat shock protein
Periodical:Nature Structural Biology
Index Medicus: Nat Struct Biol
Authors: Briknarova K, Takayama S, Brive L, Havert ML, Knee DA, Velasco J, Homma S, Cabezas, et al
Yr: 2001 Vol: 8 Nbr: 4 Abs: Pg:349-352