Functionotherapeutics: Gene Discovery and Function based Therapeutic Strategies

PROSTATE CANCER, EWING SARCOMA, BREAST CANCER, LUNG CANCER, OVARIAN CANCER, PANCREATIC CANCER

Dr E. Shyam P. Reddy,
Functionotherapeutics,
Professor and Director, Cancer Biology Program, Dept of OB/GYN, Morehouse School of Medicine, 720 Westview Drive
Atlanta, GA 30310
United States
ph: 404-756-5230
fax: 678-623-5999
ereddy@msm.edu

News Continued

National Breast Cancer Awareness Month (October)

Dr. Rao Leads Groundbreaking Breast Cancer Research

Morehouse School of Medicine is on a mission to discover the cause and cures of health inequities and new research, led by Veena N. Rao, Ph.D., professor of Obstetrics & Gynecology and co-director of the Cancer Biology Program, is a good example of the institution’s commitment to find causes and cures for breast cancer.

The research explains why African-American women have a greater risk of developing more aggressive and difficult-to-treat forms of breast cancer. Rao’s research findings reveal young African-American women with triple negative breast cancers who have cytoplasmic mislocalization of BRCA1 proteins often develop BRCA1-associated hereditary and sporadic breast cancers. Her study could lead to the discovery of novel biomarkers that can predict disease progression and validate this increased risk for African-American women.

Since the discovery of the breast cancer gene in 1994, researchers have come a long way in unlocking how various forms of breast cancer develop and in creating targeted treatment therapies. Dr. Rao, recipient of the Georgia Cancer Coalition Distinguished Cancer Scholar Award, has spearheaded numerous breakthroughs in breast cancer research including the identification of short form BRCA1 proteins known as BRCA1a and BRCA1b – which are expressed at reduced levels in breast and ovarian cancers. Her team was the first to show BRCA1a induces cell death in breast cancer cells and the first to introduce BRCA1a into triple negative breast cancer by gene therapy and successfully block tumor development in mice. Since she began her lab work in 1994, Rao has received five patents for her research findings.

The research is funded by the Georgia Cancer Coalition Distinguished Cancer Scholar Award, NIH, U54, RCMI, ACTSI and ING Foundation and published in Volume 226, Issue 12, of the Journal of Cellular Physiology.

BRCA1 proteins control growth of TNBC by tethering to Ubc9

BRCA1 dysfunction results in triple negative breast cancers (TNBC) in young African American (AA) women. BRCA1 is a nuclear-cytoplasm shuttling protein and the reason for the loss of nuclear BRCA1 localization in AA women with TNBC is not yet known. BRCA1, unlike cancer–predisposing mutant BRCA1 proteins bind to Ubc9 and modulate ER-α turnover. Qin et al have further investigated the consequence of altered Ubc9 binding and found cytoplasmic localization of disease associated mutant BRCA1 and BRCA1a proteins. Down regulation of Ubc9 using siRNA resulted in enhanced cytoplasmic retention of BRCA1 proteins. These BRCA1 mutants were clonogenic in soft agar and were seen to have an impaired ability to inhibit the growth of TNBC cells. Studies reveal a novel BRCA1 nuclear trafficking pathway that involves Ubc9 which, when disrupted, could result in breast cancer. This study suggests for the first time that the exclusive non-nuclear distribution of mutant BRCA1 and BRCA1a proteins causes deregulated Ubc9 resulting in breast cancer. These results suggest a molecular interplay between BRCA1 and Ubc9 which maintains the balance of two opposing effects: tumor suppression or tumorigenesis. BRCA1 dysfunction could tilt this delicate balance resulting in ER-α positive or ER-α negative breast cancer.

(Qin et al., J. Cell Physiology, 2011).

Dr. Veena Rao Receives Association of Scientists of Indian Origin in America
2011 Mario Toppo Distinguished Scientist Award

Veena N. Rao, Ph.D, professor in the department of Obstetrics & Gynecology, co-director of the Cancer Biology Program, and Georgia Cancer Coalition Distinguished Cancer Scholar, is the recipient of the 2011 Mario Toppo Distinguished Scientist Award from the Association of Scientists of Indian Origin in America (ASIOA). Presented at the 29th annual banquet on April 11, 2011 in Washington DC, the award recognizes an outstanding senior scientist of Indian origin for contribution to the sciences. Dr. Rao (the first woman scientist to receive this award) was recognized for her research on how BRCA1 dysfunction causes cancer health disparities in African American women with triple negative breast cancers (TNBC). Ms. Meera Shankar, the Honorable Ambassador of India was the Chief Guest.

About the Association of Scientists of Indian Origin in America (ASIOA)

ASIOA is a non-profit organization and its mission is to promote professional interaction among biomedical scientists of Indian origin living in America, Canada and India. Its purpose is to promote fellowship among scientists of Asian Indian Origin, to act as a scientific and educational society, to establish open channels of communication among all scientists, and to act as a fraternal organization and a charitable association.

New Research at Morehouse School of Medicine Unravels Enigma as to Why BRCA1 Dysfunction Results in ER-Negative Breast Cancers

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.

Morehouse School of Medicine Distinguished Cancer Researcher Named to International Breast Cancer Journal Editorial Board

Professor and Co-Director of the Cancer Biology Program, and Georgia Cancer Coalition (GCC) Distinguished Cancer Scholar from the Department of Obstetrics and Gynecology at Morehouse School of Medicine (MSM) Veena N. Rao, Ph.D., has been selected as an editorial board member of the Bentham Open The Open Breast Cancer Journal - an open access online journal that publishes original research articles on basic and clinical breast cancer research. The online publication also is considered a peer reviewed journal, provides complete and reliable information on current developments in the field.

"This new online publication is truly international in scale and is free and readily available to a worldwide audience," said Rao. "This access to cancer research information will assist in getting critical and credible preventive and treatment options to millions of people."

In March 2007, Rao and her co-investigators demonstrated for the first time - using a gene therapy strategy - that introducing the BRCA1a protein into triple-negative breast, ovarian and prostate cancers stops tumor development.

"Triple-negative breast cancers are more common among young African-American and Hispanic women, and currently there are no effective treatments against these cancers," said Rao. "Results from these studies (reported in the journal Oncogene) will provide new treatments in the future for one of the biggest needs in breast cancer research."

Rao is a recipient of the 2005 Emerald's Honor Senior Investigator Award and the 2006 Science Spectrum magazine Trailblazer Award - an honor given to outstanding Hispanic, Asian American, Native American, and Black professionals in the science arena whose leadership and innovative thinking on the job and in the community extend throughout and beyond their industry. In 2007, she also was honored with the National Women of Color in Technology Research Leadership Award. She also has been featured on the NCI Web site under the "NCI Grantee Spotlights."

http://www.msm.edu/News/News_Index/21109_am.htm

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