Breast cancer is the most frequent type of cancer in women in Western societies and in the United States has shown an alarming increase in incidence from 87/100,000 to 104/100,000 within the last five years. It is commonly accepted that early diagnosis and treatment of breast cancer results in a more favorable prognosis; however, despite the increase use of mammography and breast self-examination, the morality from breast cancer has remained constant. At present there is no specific biological tumor marker for breast cancer. Recent studies have suggested that peptide growth factors may play a critical role in modulating both normal and abnormal cellular proliferation and may have potential as biological tumor markers. During our prior granting period, we identified specific growth factor activities in milk of substrains of mice with varying incidences of developing mammary tumor. The specific growth factor activities were present only in milk of mice that had or eventually developed mammary tumor. None of the milk from control mice contained these specific growth factor activities. Chemical characterization has shown these specific growth factor activities to be acid- and heat-stable and resistant to reducing agents. Partial purification of these specific predictive growth factor activities by ion exchange, HPLC, isoelectrofocusing and radioimmune assay has identified the major components to be IGF-1 related peptide(s). We studies breast cyst fluid from 35 women and found growth factor activities similar to those found in murine milk. Breast cyst fluid when analyzed for total mitogenic activity indicated a direct relationship with a woman's risk of developing breast cancer. The highest risk group demonstrated a 28 fold increased mitogenic activity compared to the lowest risk women (14,000 mitogenic units/ml versus 500 mitogenic units/ml). Similar growth factor activities were also found in human breast cancer tissue. We hypothesize that and IGF-1 immunoreactive peptide(s) is present early in the development of breast cancer, and the identification of this growth factor can be used as a biological tumor marker predictive of malignancy. We propose to purify, identify, and compare the IGF-1 immunoreactive peptide(s) predictive of murine mammary tumor development and the components of the similar specific mitogenic activity present in human breast cancer tissue and human breast cyst fluid by standard protein purification techniques and peptide microsequencing analysis. We also will determine the correlation of these IGF-1 related peptide(s) in breast cyst fluid, as measured by radioimmune assay, with the differing risk of women developing breast cancer. The identification of these specific growth factors might provide a much needed early screening system for assessing the risk of developing breast cancer in the form of a simple laboratory assay using body fluids as the test material. iN addition, the proposed research may lead to the development of immunotherapeutic tools.
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