Abstract 1282: Comparison of serum progesterone levels of the immunomodulatory protein, the progesterone induced blocking factor, in people with BRCA-2 mutations associated with and not associated with a high risk of cancer

Abstract

Abstract The BRCA genes normally provide proteins important in degradating the progesterone (P) receptor. BRCA1 and 2 mutations may make mutated protein, leading to prolongation of P receptor activity which may be involved in the mechanism of how these mutations increase the risk of breast and ovarian cancer. The progesterone induced blocking factor (PIBF) is a protein which suppresses natural killer (NK) cell cytotoxicity, and exposure to P increases both serum levels of PIBF and intracytoplasmic levels in rapidly growing cells (both fetus and cancer cells). The objective of this study was to compare serum PIBF levels in a person with a wild type BRCA2 mutation not known to be associated with malignancy versus the familial type of BRCA2 mutation associated with malignancy. Serum levels of PIBF were obtained in the follicular phase x5 in a woman with a benign wild type heterozygote mutation of BRCA2 (NM000059.3 C.1964 (>(P655R) and in two anovulatory women and a man with familial BRCA2 mutations associated with increased risk of malignancy. The PIBF assay was a research ELISA method using a monoclonal antibody to PIBF. All 5 serum samples of the 21 year old woman with the benign BRCA2 mutation were over 700 ng/mL (levels seen only with high levels of serum P) vs. an average of 55.5 in 2 women with breast cancer at an early age and 1 man positive for the familial BRCA2 mutation. The high levels of serum PIBF seen with the wild type heterozygote mutation show that certain types of BRCA mutations can be associated with increased PIBF levels. Perhaps this BRCA2 wild type mutation is more associated with interfering with degradation of the P receptor found in gamma delta T cells, thus increasing serum PIBF levels. Increased virulence of certain cancers, e.g., breast cancer, has been found with increasing P receptor longevity by either phosphorylation or decreased ubiquitination or sumoylation. Blocking P receptor activity by certain P receptor antagonists, e.g., mifepristone, has been shown to decrease tumor virulence irrespective of the presence or not of P receptors in the tumor. The parent compound for PIBF is a 90 kDa nuclear protein found in the centrosome, but it can be converted to 34-36 kDa immunoprotective intracytoplasmic protein which is similar or identical to the circulating PIBF. Conditions associated with consistent high levels of serum PIBF, e.g., grand multiparous women, are not associated with increased risk of malignancy. Thus an attractive hypothesis (that needs to be proven) is that the BRCA2 mutation (and maybe BRCA1 also) leads to prolongation of the nuclear P receptor leading to increased nuclear PIBF, resulting in increased intracellular PIBF, which, in turn, helps protect the cancer cells especially from NK cell immunosurveillance but potentially other immune factors also. Citation Format: Jerome H. Check, Michael P. Dougherty, Gabrielle DiAntonio, Jamie Vaniver, Marie Duroseau, Maya D. Srivastava. Comparison of serum progesterone levels of the immunomodulatory protein, the progesterone induced blocking factor, in people with BRCA-2 mutations associated with and not associated with a high risk of cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1282. doi:10.1158/1538-7445.AM2015-1282