Dr. Walker is internationally recognized as a leader in developmental reprogramming and has been instrumental in defining this new field, which seeks to understand how environmental exposures early in life increase risk of disease in adulthood. She was the first to demonstrate that chemical carcinogens can target tumor suppressor genes, leading the field that had previously focused on oncogene activation as mechanisms of carcinogenesis in an entirely new direction focusing on inhibition of tumor suppressors (Walker et al Science, 1992). Her long-standing interest in this area formed the foundation for more recent studies where she identified developmental reprogramming as a novel mechanism by which environmental exposures modulate the penetrance of a tumor suppressor gene defect (Cook et al Proc Natl Acad Sci 2005). In these recent studies, she showed that even brief exposure to environmental xenoestrogens early in life while tissues and organs are developing increases the risk of developing cancer at these sites later in adult life. She has gone on to show that this increased risk is the result of changes in the epigenome that reprogram genes that promote tumor development (Bredfeldt et al Mol. Endo. 2010). This most recent paper established for the first time a direct link between environmental xenoestrogens and the cells’ epigenetic machinery, identifying an important new mechanism by which environmental exposures in childhood can influence risk of developing disease, including cancer, in adulthood. Her research provides a mechanism for developmental reprogramming of disease susceptibility, offering the potential to use epidentic “marks” as biomarkers of early life exposure and/or future risk of disease. Importantly, as reversible epigenetic alterations, suggest that it may be possible to reverse the effects of developmental programming via interventions that modulate environmentally-induced epigenetic effects.
Mouse In addition to her work on developmental reprogramming, Dr. Walker has furthered our understanding of mechanisms responsible for kidney, prostate and uterine cancer. She is an internationally recognized leader in uterine leiomyoma research, an important and understudied disease of women (Walker and Stewart, Science, 2005). Dr. Walker developed the “gold-standard” animal model used by numerous academic and pharmaceutical labs for studying uterine leiomyoma to identify the molecular basis and develop novel therapeutic agents for this disease. Dr. Walker was the first to report that Eker rats with a defect in the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene developed spontaneous uterine leiomyoma and established a panel of hormonally responsive cell lines from these tumors that could be used in concert with the genetically susceptible rats as an in vitro/in vivo model for preclinical studies on this disease. Her findings have made a significant contribution to the identification of novel therapeutic agents for this disease, and as such, have had a significant impact on uterine leiomyoma therapy, with the potential to improve the quality of life and reduce the number of hysterectomies for women (Crabtree et al. Can. Res. 2010).
2010 Sciences Cozzarelli Prize Winners Finally, the innovative work being done in Dr. Walker’s lab in the area of cell signaling pathways that regulate the TSC2 tumor suppressor is providing new scientific insights and shifting existing paradigms. She recently identified a new signaling node connecting damage responses in cells to regulation of their growth with her discovery of a new role for the DNA repair protein ATM in the cytoplasm. ATM, the gene mutated in the genetic disease ataxia telangiectasia (AT), is a well-known protein involved in the DNA double-strand break response, where it plays an important role in the nucleus in DNA damage response. Dr. Walker’s group was the first to report that ATM also functions in the cytoplasm (Alexander et al., Proc. Natl. Acad. Science, 2010). Her research into mechanisms of Tuberous Sclerosis complex (TSC) tumor suppressor regulation helped uncover a pathway upstream of TSC that is regulated by cytoplasmic ATM in response to oxidative damage. TSC2 activation by ATM results in mTORC1 repression and subsequent induction of autophagy. She was recently awarded the prestigious 2010 National Academy of Sciences Cozzarelli Prize for her groundbreaking work on ATM signaling to TSC.
As a widely recognized leader in the areas of developmental reprogramming and environmental epigenomics, her knowledge and insight are sought by numerous national and international advisory committees. Her previous appointments include the Board of Scientific Councilors of the National Cancer Institute, the Board of Scientific Councilors of the National Toxicology Program, and the Oncological Sciences Boundary Setting Team for realignment of NIH study sections. She has served as Invited Expert for the BK-Tox Advisory Committee on Dangerous Substances, Labor Ministry of Germany, Member of the WHO Working Group on Public Health and Clinical Significance of Premalignant Lesions in the Genitourinary Tract, Member of the National Academy of Sciences Committee on Emerging Issues and Data on Environmental Contaminants and Member of the Committee on Breast Cancer and the Environment of the Institute of Medicine.
The quality and quantity of her body of work show outstanding scholarship and as such, her work has had a strong impact on the scientific discourse on environmental health. She has a sustained, impactful publication record with over 125 peer-reviewed articles in high-impact journals such as Science, Molecular Cell, Nature Cell Biology and Proceedings of the National Academy of Sciences of the United States of America and is frequently invited to speak at other institutions and scientific meetings, nationally and internationally. Her success is further evidenced by a strikingly successful funding record.
Dr. Walker also has a record of leadership in not one, but two large professional societies. She has held elected and appointed positions in the American Association for Cancer Research, including being elected President of Women in Cancer Research. Similarly, she has held numerous leadership positions in the Society of Toxicology, including election by the membership to their Board of Directors and most recently, President of the Society. Dr. Walker was the 4th women to serve as President and her 4 years in leadership were marked by times of increasing diversity, inclusivity and scientific advancements in toxicology. She has also been elected a Fellow of the Academy of Toxicological Sciences.