Autoantibodies in Breast Cancer

Institution: Scripps Research Institute
Investigator(s): Robert Ochs, Ph.D. -
Award Cycle: 1997 (Cycle III) Grant #: 3IB-0083 Award: $130,130
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (1997)
Initiation and progression of breast cancer is believed to include the expression of novel and mutated cellular proteins. We plan to examine the blood of women with breast cancer for the presence of circulating autoantibodies to tumor proteins. Our initial studies revealed a wide spectrum of immunologic responses to specific protein antigens. Blood from 158 patients with breast cancer were initially screened using indirect immunofluorescence (a visual analysis giving cellular location) and immunoblotting (detects specific proteins) against breast cancer (T47D) cell and whole-cell extracts. Autoantibodies were detected in 78/158 of the sera samples. We are able to detect the location within the cell (e.g., nucleus, cytoplasm, mitochondria) where the autoantibodies bind. These autoantibodies may be targeting important proteins known to be involved in cancer, such as the p53 tumor suppressor protein, but most of them remain to be fully identified. Interestingly, a few patients had autoantibodies that recognized certain proliferation-associated proteins (NuMA and PCNA) not previously described in breast cancer. In summary, we believe that breast cancer may be rendering some molecules immunogenic and generating antibodies that, although not effective in combating the disease, might still be instructive in identifying novel proteins involved in malignancy.

In this project we will explore and further characterize the autoantibody specificities in the blood of women with breast cancer, and focus on comparing malignant to benign disease. The autoantibody specificities will continue to be determined by immunofluorescence microscopy and Western blotting. Once the autoantibody specificity of a breast cancer patient is characterized, we will then compare these to the clinical information to associate them with disease type, severity, prognosis, and outcome. Our long-term goal is to link information on autoantibody status (i) to achieve an earlier diagnosis, (ii) as a predictor of disease progression, and (iii) as a guide to select the appropriate treatment therapy. In addition to their direct clinical application, autoantibodies found in the blood of breast cancer patients could aid in the discovery of novel oncogenic proteins that are involved in the pathophysiology of breast cancer.

Final Report (1998)
Autoantibodies in cancer patients appear to increase in amount, immediately preceding or coincident with the malignancy. It seems likely that these autoantibodies represent an immune response to abnormally altered (i.e., mutated) or overexpressed proteins.

We have examined the sera of women with breast cancer for the presence of autoantibodies that may be a reflection of an immunogenic response. In our initial studies, 49% of the 157 breast cancer patients obtained through Duke University had autoantibodies detected by immunofluorescence and/or immunoblotting. A number of different autoantibody types were present, including antibodies against nucleoli, nuclear bodies, mitochondria, and the mitotic apparatus. Thus far, autoantibodies have been identified against , (i) the tumor suppressor protein, p53, (ii) NuMA, a protein involved in nuclear reorganization after mitosis, and (iii) PCNA, a proliferation-related component of the enzyme complex used to synthesize DNA. Most of the other autoantibodies await further molecular characterization. In the present study we extended these observations to additional breast cancer samples obtained at the Scripps Clinic and through a collaborator in Brazil. In all the different patient groups examined, the presence of autoantibodies was present in about one-half. Our initial attempts to correlate our findings with clinical parameters has not been informative. Our next goal is to gain a more detailed understanding of the specific antigens recognized by these autoantibodies. Hopefully, these results will correlate better with certain clinical parameters.

Information on autoantibody status could be useful for earlier diagnosis, as a predictor of disease progression, and as a guide to select the appropriate treatment therapy.