New Research at Morehouse School of Medicine Solves Breast Cancer Puzzle

5/22/2009

Morehouse School of Medicine's (MSM) researchers have solved one of the biggest puzzles in breast cancer research - how and why BRCA1 dysfunction results in tissue-specific breast and ovarian cancers. The health implications of this study in cancer health disparities are truly immense. According to the results by Veena N. Rao, Ph.D. professor and co-director of the Cancer Biology Program, in the Department of Obstetrics and Gynecology of MSM, Georgia Cancer Coalition distinguished cancer scholar, the paper reveals why women with alterations in the BRCA1 gene often develop Estrogen-receptor negative breast cancers, which could potentially lead to function-based cellular assays that can validate their risk for developing these aggressive breast cancers, where she served as senior author, will be published in the April 2009 online issue of International Journal of Oncology, Volume 34, No 4. The study suggests for the first time that the reason women with BRCA1 dysfunction get hormone-responsive cancers like breast and ovarian is that BRCA1 regulates the dynamic cycles of SUMO and Ubiquitin modifications required for Estrogen receptor-alpha turn over and deregulation of this molecular switch due to lack of BRCA1 results in Estrogen receptor-negative and positive breast cancers. BRCA1 dysfunction results in hereditary and sporadic breast cancers. Majority of the women with BRCA1 mutations are estrogen receptor-negative, progesterone receptor-negative and HER-2 receptor-negative (Triple Negative breast cancers).TN breast cancers are highly aggressive, more common in young African-American women, have higher rates of distant metastasis and currently there are no targeted treatments against these cancers. There is significant overlap between TN breast cancers and BRCA1 associated breast cancers that suggests that dysfunction in the BRCA1 pathway may be responsible for the development of these cancers. Rao's team has previously identified two short forms of BRCA1 protein named BRCA1a and BRCA1b, which are expressed at reduced levels in breast and ovarian cancers. BRCA1a and BRCA1b differ from BRCA1 in having an in frame deletion of majority of the exon 11 sequences that comprise 60 percent of the BRCA1 coding region. BRCA1b has an additional deletion of exon 9 and 10 sequences. They have previously shown that inhibition of expression of this protein in normal cells results in cancer and high level of expression of which results in cell death and growth inhibition of TN breast cancers, ovarian and prostate cancers. The researchers have found SUMO-E2-conjugating enzyme Ubc9 to be a new binding partner for BRCA1, BRCA1a and BRCA1b proteins. Mutation in the Ubc9 binding site as well as BRCA1 RING domain cancer-predisposing mutation (C61G) disrupted the ability to both bind as well as modulate Ubc9 mediated SUMO-dependent/independent estrogen-induced ER-alpha transcriptional activity in breast cancer cells. The researchers have shown for the first time BRCA1 protein to function as a novel SUMO-1 and Ubc9-dependent E3 ubiquitin ligase for ER-alpha. These studies show that BRCA1 represses levels of ER-alpha by promoting its degradation. BRCA1 belongs to a new family of RING-finger proteins that link both the SUMO and Ubiquitin pathways. "We believe that binding of SUMO-tagged ER-alpha to Ubc9 could serve as a signal for BRCA1 proteins to target it for degradation and impairment of this function can results in breast and ovarian cancers" says Rao. "Our future efforts will be geared towards studying BRCA1 protein function in a totally new direction." These findings uncover the paradox as to why BRCA1 dysfunction leads to TN breast cancers as well as develop novel targeted therapies based on enhancing the degradation of stalled ER-alpha to reinitiate transcription offers a promising method for the treatment of these ER-negative breast cancers. Other researchers participating in this study include Shyam P. Reddy, Ph.D., professor and co-director of the Cancer Biology Program and Georgia Cancer Coalition distinguished cancer scholar; Jiang Xu, M.D., and Tameka Watkins, M.S. Rao received the 2005 Science Spectrum Emerald Honors Senior Investigator Award, the 2006 Science Spectrum Trail Blazer Award, the 2007 Women of Color in Technology Research Leadership Award, and the 2008 North American Konkini Association Outstanding Achievement in Science Award. Recently she was appointed as an editorial board member of the Open Breast Cancer Journal. The technologies dealing with the novel cell-based assays and other related technology developed in Rao's laboratory at MSM will be available for commercialization. This work was funded by Georgia Cancer Coalition Distinguished Cancer Scholar Award. For more information about the Georgia Cancer Coalition’s Distinguished Cancer Scholar Award program, please click here .