Immune responses to breast cancers: function of TRAF protein

Institution: The Burnham Institute for Medical Research
Investigator(s): John Reed, M.D., Ph.D. - John Reed, M.D., Ph.D. - John Reed, M.D., Ph.D. - John Reed, M.D., Ph.D. -
Award Cycle: 1996 (Cycle II) Grant #: 2RB-0215 Award: $284,581
Award Type: Research Project Awards
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (1996)
It has been estimated that potentially cancerous cells arise in our bodies nearly every day. Fortunately, however, cells within our immune systems are able, in most cases, to eradicate these abnormal cells before they have an opportunity to form lethal tumors. For over 100,000 women each year in this country alone, the immune defense mechanisms against tumors fail where carcinomas of the breast are concerned.

The goal of this proposal is to provide new insights into some of the mechanisms by which immune cells can attack and kill cancerous cells. Most immune cells attack tumors by producing proteins that bind to receptors on the target cancer cells. These receptors, in turn, deliver signals into tumor cells which activate a latent program for cell suicide. Understanding more about the mechanisms by which these suicide receptors function has the potential to provide novel insights that might be exploited clinically to enhance immune responses to breast cancers.

Some of the most important suicide receptors are members of the Tumor Necrosis Factor (TNF) Receptor family. Little is known, however, about how these receptors deliver signals into tumors that kill them. Recently, we and others have discovered a group of closely related proteins that interact with TNF-family receptors, called TNF-Receptor Associated Factor (TRAF) proteins. The purpose of this proposal is to understand the mechanisms by which these TRAF proteins transfer signals from the suicide receptors into breast cancer cells. The results of these investigations may provide mechanistic insights that lead to novel therapeutic approaches to breast cancer treatment and prevention.

Final Report (1998)
The goal of this proposal is to understand some of the mechanisms used by the immune system to attack and eradicate tumor cells. Currently available therapies for breast cancer rely on cytotoxic agents and x irradiation, which potentially can kill tumor cells but also harm normal tissues. In contrast, if the power inherent within the immune system could be harvested, then it might be possible to specifically eliminate tumor cells without undue damage to normal tissues.

We proposed to investigate the mechanisms by which immune modulatory receptors found on the surface of tumor cells convey information from outside the cell to the interior, resulting in changes in gene activity and modifications of biochemical events that result in either tumor cell death or that conversely promote tumor cells survival. Our goal was to identify ways of making tumor cells more vulnerable to immune system attack. Our investigations yielded several novel insights into the mechanisms that tumor cells can use to thwart the efforts of the immune system. We found that a group of proteins (called IAPs) within tumor cells bind to cell death proteases and prevent immune mediated tumor destruction. We also found that breast cancers sometimes alter their levels of key signaling proteins (called TRAFs) that are needed for sensitivity to the receptors that the immune system relies upon for influencing breast cancers.

As a result of this grant, we now understand some of the reasons why breast cancer cells can be difficult to eliminate by the immune system. The biochemical mechanisms uncovered reveal new strategies for perhaps developing drugs that might overcome the resistance of breast cancers to the immune system, and thereby improving chances of marshaling the body's own defense systems for eliminating or controlling breast cancer.

Expression of multiple apoptosis-regulatory genes in human breast cancer cell lines and primary tumors
Periodical:Breast Cancer Research and Treatment
Index Medicus: Breast Cancer Res Treat
Authors: Zapata JM, Krajewska M, Krajewski S, Huang R-P, Takayama S, and Reed JC, et al
Yr: 1998 Vol: 47 Nbr: Abs: Pg:129-140

Immunohistochemical analysis of in vivo patterns of TRAF-3 expression, a member of the TNF receptor-associated factor family
Periodical:Journal of Immunology
Index Medicus: J Immunol
Authors: Krajewski S, Zapata JM, Krajewksa M, VanArsdale T,Shabaik A, and Reed JC, et al
Yr: 1997 Vol: 159 Nbr: Abs: Pg:5841-5852

The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases
Periodical:Embo Journal
Index Medicus: EMBO J
Authors: Roy N, Deveraux QL, Takahashi R, Salvesen GS and Reed JC
Yr: 1997 Vol: 16 Nbr: 23 Abs: Pg:6914-6925

Differences in susceptibility to tumor necrosis factor alpha-induced apoptosis among MCF-7 breast cancer cell variants
Periodical:Cancer Research
Index Medicus: Cancer Res
Authors: Burow ME, Weldon CB, Tang Y, Navar G, Hammond T, Krajewski S, and Reed JC, et al
Yr: 1998 Vol: 58 Nbr: 21 Abs: Pg:4940-4946

Granzyme release and caspase activation in human T-lymphocyts
Periodical:Journal of Biological Chemistry
Index Medicus: J Biol Chem
Authors: Zapata JM, Takahashi R, Salvesen GS, and Reed JC
Yr: 1998 Vol: 273 Nbr: 12 Abs: Pg:6916-6920

IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases
Periodical:Embo Journal
Index Medicus: EMBO J
Authors: Deveraux Q, Roy N, Stennicke HR, Zhou Q, Srinivasula SM, and Reed JC at el
Yr: 1998 Vol: 17 Nbr: 8 Abs: Pg:2215-2223

TRAF-4 expression in epithelial progenitor cells: Analysis in normal adult, fetal, and tumor tissues
Periodical:American Journal of Pathology
Index Medicus: Am J Pathol
Authors: Krajewska M, Krajewski S, Zapata JM, Van Arsdale TGascpume R, an Reed JC
Yr: 1998 Vol: 152 Nbr: 6 Abs: Pg:1549-1561

X-linked IAP is a direct inibitor of cell-death poteases
Index Medicus: Nature
Authors: Deveraux Q, Takahashi R, Salvesen GS, and Reed JC
Yr: 1997 Vol: 388 Nbr: 6639 Abs: Pg:300-4