DEGRAFFENRIED, LINDA A

Linda A Degraffenried

Associate Professor
Department of Nutritional Sciences


degraffenried@austin.utexas.edu

Phone: 512-495-3016

Office Location
DPI 2.806

Postal Address
The University of Texas at Austin
Department of Nutritional Sciences, College of Natural Sciences
103 W 24TH ST A2703
PAI 5.20
Austin, TX 78712

Ph.D., University of Texas Health Science Center at San Antonio
B.A., Colgate University

While recent improvements in detection and treatment have improved the overall survival rate for breast cancer, it remains the second leading cause of cancer-related deaths for women in the US. This is primarily due to our lack of understanding as to the mechanisms by which cancer cells develop an aggressive phenotype, becoming resistant to most therapies and metastasizing to distant sites such as the bone and lungs. Similarly, while surgery successfully cures 90% of all prostate cancers, those cancers that recur and metastasize are highly resistant to all our current treatments, resulting in death within 5 years in 96% of the men with recurrent disease. The deGraffenried laboratory investigates the mechanisms by which breast and prostate cancer cells become highly aggressive, focusing on the signaling that occurs within the cell to promote survival of the cancer cell even in the face of treatment that should promote death of the cancer cell. By understanding the mechanisms by which cells become aggressive, we hope to develop effective interventions that will block these processes. We investigate both pharmacological as well as diet and lifestyle approaches to modulate the cancer process, in the hope of inhibiting both the development of the cancer as well as improving treatment response in the more resistant tumors.

We are extremely interested in how obesity, a rising epidemic within the US, influences survival of breast and prostate cancer patients. We are working with clinicians at the Health Science Center at San Antonio as well as at the University of Kansas Cancer Center to understand how obesity promotes worse outcome in breast and prostate cancer patients, both in terms of increasing the risk of developing the disease as well as making the tumors that develop in obese patients much less responsive to treatment. In a highly collaborative effort, we are working together to move the findings in the laboratory quickly into the clinic, and taking the results from the clinic back to the laboratory to develop even better therapeutics for treating these deadly cancers.

We are also interested in how the aging process influences the development of prostate cancer, and are using highly novel models to understand the relationship between aging, the immune system, and prostate cancer development. The aging immune system not only is compromised in terms of its ability to fight off infection, but it also changes in terms of the factors that are secreted from the immune cells, promoting changes in the prostate tissue that make it more susceptible to the development of cancer. Our highly novel studies have provided significant insight as to why the risk for prostate cancer rises dramatically in older men but is never seen in younger men. The ultimate goal is to develop diagnostic assays that could detect the presence of the cancer-promoting factors in the blood and provide compounds that could inhibit the activity of these factors.

Finally, for several years we have been investigating the potential use of omega-3 fatty acids, found in high quantities in marine fish oil, to improve patient outcome, both in terms of improving tumor response to conventional therapies as well as functioning as cancer preventive agents in women at high risk for the development of breast cancer. Our preclinical data suggests that properties of the omega-3 fatty acids are associated with suppression of the pathways needed by the cancer cells to survive, while not affecting the health of non-cancer cells. We are involved in clinical investigations with high risk patients to determine if omega-3 fatty acid supplementation can prevent the development of invasive breast cancer as well as recurrent prostate cancer. Additionally, we are also working with the clinicians to evaluate the use of omega-3 fatty acids to improve tumor response to hormone therapy in both resistant breast and prostate cancer.

The deGraffenried laboratory is part of an integrated program that encompasses basic research, cancer treatment, clinical trials, education programs and cancer prevention. The ultimate goal is to develop effective interventions, both pharmacological as well as diet and lifestyle that lower both the risk as well as aggressiveness of breast and prostate cancer, leading to improved survival for all cancer patients.

Dr. deGraffenried has been nationally and internationally recognized for her work in breast and prostate cancer. She receives funding for her work from the National Cancer Institute, the American Institute for Cancer Research, the Susan G. Komen for the Cure Foundation, and the Department of Defense. She sits on several national review panels, and is an associate editor for the journal Molecular Carcinogenesis. Dr. deGraffenried’s students have received recognition for the research that they are doing in her laboratory, including full fellowships for their graduate studies as well as numerous travel awards to present their research at national meetings.

Selected publications

  1. Yang, F., Friedrichs, W. E., Navarijo-Ashbaugh, A. L., deGraffenried, L. A., Bowman, B. H., and Coalson, J. J. Cell type-specific and inflammatory-induced expression of haptoglobin gene in lung, Lab Invest. 73: 433-40., 1995.
  2. Yang, F., Friedrichs, W. E., deGraffenried, L., Herbert, D. C., Weaker, F. J., Bowman, B. H., and Coalson, J. J. Cellular expression of ceruloplasmin in baboon and mouse lung during development and inflammation, Am J Respir Cell Mol Biol. 14: 161-9., 1996.
  3. Dechaud, H., Witz, C. A., Montoya-Rodriguez, I. A., Degraffenreid, L. A., and Schenken, R. S. Mesothelial cell-associated hyaluronic acid promotes adhesion of endometrial cells to mesothelium, Fertil Steril. 76: 1012-8., 2001.
  4. deGraffenried LA, Hilsenbeck SG, Fuqua SAW: Sp1 is essential for estrogen receptor alpha gene transcription. J Steroid Biochem Mol Biol 82(1): 7-18, 2002.
  5. Grünwald, V., deGraffenried, L., Russel, D., Friedrichs, W. E., Ray, R. B., and Hidalgo, M. Inhibitors of mTOR Reverse Doxorubicin Resistance Conferred by PTEN Status in Prostate Cancer Cells. Cancer Res. 62 (21):, 2002.
  6. deGraffenried, L. A., Friedrichs, W. E., Fulcher, L., Fernandes, G., Silva, J. M., Peralba, J.-M., and Hidalgo, M. Eicosapentaenoic Acid Restores Tamoxifen Sensitivity in Breast Cancer Cells with High Akt Activity, Ann Oncol. 14: 1051-6, 2003.
  7. Malik, S. N., Siu, L. L., Rowinsky, E. K., deGraffenried, L., Hammond, L. A., Rizzo, J., Bacus, S., Brattain, M. G., Kreisberg, J. I., and Hidalgo, M. Pharmacodynamic Evaluation of the Epidermal Growth Factor Receptor Inhibitor OSI-774 in Human Epidermis of Cancer Patients, Clin Cancer Res. 9: 2478-2486, 2003.
  8. Peralba, J. M., deGraffenried, L., Friedrichs, W., Fulcher, L., Grunwald, V., Weiss, G., Rowinsky, E., Dukart, G., and Hidalgo, M. Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients, Clin Cancer Res 9(8):2887-92, 2003.
  9. deGraffenried, LA, Hopp TA, Valente AJ, Clark, RA, and Fuqua SAW. Regulation of the estrogen receptora minimal promoter by Sp1, USF-1 and ERa. Breast Cancer Res Treat, 85(2):111-120, 2004.
  10. deGraffenried, L. A., Friedrichs, W. E., Chandrasekar, B., Donzis, E., Silva, J., Hidalgo, M., Freeman, J. W., and Weiss, G. R. NF-kB Inhibition Markedly Enhances Sensitivity of Resistant Breast Cancer Tumor Cells to Tamoxifen, Ann Oncol. 15 (6):885-90, 2004.
  11. deGraffenried, LA, Friedrichs WE, Russell DH, Donzis EJ, Middleton AK, Silva JM, Roth RA, and Hidalgo M. Inhibition of mTOR Activity Restores Tamoxifen Response in Breast Cancer Cells with Aberrant Akt Activity, Clin Cancer Res, 10(23):8059-8067, 2004.
  12. deGraffenried, L. A., Fulcher, L., Friedrichs, W. E., Grünwald, V., Ray, R. B., and Hidalgo, M. Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3/Akt pathway, Ann Oncol. 15(10):1510-1516, 2004.
  13. Beeram B, Tan Q-T N, Tekmal RR, Russell D, Middleton A and deGraffenried LA. Akt-Induced Endocrine Therapy Resistance is Reversed by Inhibition of mTOR Signaling, Ann Oncol. 18:1323-1328, 2007.
  14. Silva J, Cavazos D, Donzis E, Friedrichs WE, Marciniak R, and deGraffenried LA. Akt-Induced Tamoxifen Resistance is Associated with Altered FKHR Regulation, Cancer Invest. 25:1-5, 2007.
  15. Troyer DA, Tang Y, Bedolla R, Adhvaryu SG, Thompson IM, Abboud-Werner, S Sun L-Z, Friedrichs WE, deGraffenried LA. Characterization of PacMetUT1, A Recently Isolated Human Prostate Cancer Cell Line, Prostate. 68(8):883-92, 2008
  16. Friedrichs W, Ruparel SB, Marciniak RA, and deGraffenried L. Omega-3 Fatty Acid Inhibition of Prostate Cancer Progression to Hormone Independence is Associated with Suppression of mTOR Signaling and Androgen Receptor Expression. Nutr and Cancer, 63 (5): 771-7, 2011
  17. Mishra S, Tang Y, Wang L, deGraffenried L, Yeh I-Y, Werner S, Troyer D, Copland JA, Sun L-Z.  Blockade of transforming growth factor-beta (TGFβ) signaling inhibits osteoblastic tumorigenesis by a novel human prostate cancer cell line. Prostate, 71 (13):1441-54, 2011
  18. Cavazos DA, Salcedo Price M, Apte S, deGraffenried, LA. Docohexanoic Acid Selectively Induces Human Prostate Cancer Cell Sensitivity to Oxidative Stress through Modulation of NF-κB.  Prostate, 71 (13):1420-8, 2011
  19. Tiwary R, Yu W, Degraffenried LA, Sanders BG, Kline K. Targeting cholesterol-rich microdomains to circumvent tamoxifen-resistant breast cancer.  Breast Cancer Res. 13(6):R120, 2011
  20. De Angel RE, Conti CJ, Wheatley KE, Brenner AJ, Otto G, Degraffenried LA, Hursting SD. The enhancing effects of obesity on mammary tumor growth and Akt/mTOR pathway activation persist after weight loss and are reversed by RAD001. Mol Carcinog. 2012 Jan 30. doi: 10.1002/mc.21878.
  21. Price R S, Cavazos D A, De Angel R E, Hursting S D and deGraffenried LA.  Obesity-related systemic factors promote an invasive phenotype in prostate cancer cells. Prostate Cancer Prostatic Dis (14 February 2012) | doi:10.1038/pcan.2011.54
  22. Chen CH and deGraffenried LA. Anethole suppressed cell survival and induced apoptosis in human breast cancer cells independent of estrogen receptor status. Phytomedicine. 2012 Jun 15;19(8-9):763-7
  23. De Angulo A, Faris R, Cavazos D, Jolly C, Daniel B and deGraffenried L. Age-related Alterations in T-lymphocytes Modulate Key Pathways in Prostate Tumorigenesis. Prostate. 2013 Jun;73(8):855-64. doi: 10.1002/pros.22631. Epub 2013 Mar 26
  24. Apte S, Cavazos D, Whelan K and deGraffenried L. A low dietary ratio of omega-6 to omega-3 fatty acids may delay progression of prostate cancer. Nutr Cancer. 2013;65(4):556-62. doi: 10.1080/01635581.2013.775316.
  25. Bowers LW, Cavazos DA, Maximo IXF, Brenner AJ, Hursting SD and deGraffenried LA. Obesity enhances nongenomic estrogen receptor crosstalk with the PI3K/Akt and MAPK pathways to promote in vitro measures of breast cancer progression. Breast Cancer Res. 2013 Jul 23;15(4):R5927.
  26. Bowers LW, Maximo IXF, Brenner A, Beeram M, Hursting SD, Price RS,. Jolly C, Tekmal RR, deGraffenried LA. NSAID Use Attenuates Breast Cancer Recurrence in Overweight and Obese Women: Role of Prostaglandin-Aromatase Interactions. Cancer Res. 2014 Aug 15;74(16):4446-57. doi: 10.1158/0008-5472.CAN-13-3603
  27. Cavazos DA, deGraffenried MJ, Whelan K, Bowers LW, Price RS, Apte S and deGraffenried LA. Obesity Promotes Aerobic Glycolysis in Prostate Cancer Cells. Nutr Cancer, 2014 DOI: 10.1080/01635581.2014.951738
  28. De Angulo A, Faris R, Jolly C, Daniel B, deGraffenried L. Age-related Increase in IL-17 Activates Pro-inflammatory Signaling in Prostate Cells, Prostate. 2015 Apr 1;75(5):449-62. doi: 10.1002/pros.22931. Epub 2015 Jan 5.
  29. Faris R, Fan Y-Y, De Angulo A, Chapkin RS, deGraffenried L and Jolly C. Mitochondrial Glycerol-3-Phosphate Acyltransferase-1 is Essential for Murine CD4+ T Cell Metabolic Activation, Biochim Biophys Acta. 2014 Oct;1842 (10):1475-82. doi: 10.1016/j.bbalip.2014.07.009. Epub 2014 Jul 24
  30. Bowers LW, Brenner AJ, Hursting SD, Tekmal RR, deGraffenried LA. Obesity-associated systemic interleukin-6 promotes pre-adipocyte aromatase expression via increased breast cancer cell prostaglandin E2 production. Breast Cancer Res Treat. 2014 Dec 5. [Epub ahead of print]
  31. Bowers LW and deGraffenried LA. Targeting the COX-2 Pathway to Improve Therapeutic Response in the Obese Breast Cancer Patient Population. Current Pharmacology Reports. 2015. DOI: 10.1007/s40495-015-0041-y
  32. Bowers LW, Rossi E, O'Flanagan C, deGraffenried L, Hursting S. The role of the insulin/IGF system in cancer: lessons learned from clinical trials and the energy balance-cancer link. Front Endocrinol (Lausanne). 2015 May 15;6:77. doi: 10.3389/fendo.2015.00077
  33. Ford N, Rossi E Brown P; Yang P, Bowers L, Hidaka B, Kimler B, Carlson S, Ishireqi Degraffenried LA, Fabian C, Hursting S. Omega-3-Acid Ethyl Esters Block the Protumorigenic Effects of Obesity in Mouse Models of Postmenopausal Basal-Like and Claudin Low Breast Cancer. Cancer Prev Res (Phila). 2015 Jun 22. pii: canprevres.0018.2015.
  34. Bowers LW, Wiese M, Brenner A, Tekmal RR, Rossi EI, Hursting SD, deGraffenried LA. Obesity Suppresses Estrogen Receptor Beta Expression in Breast Cancer Cells Via HER2. Endocrine-Related Cancer. 2015 under review

 

Book Chapters

1.       Cavazos, D. A., Apte, S. A., Chen, C. H., and deGraffenried, L. A. (2013) Omega-3 Fatty Acids Target NF-kB to Modulate Breast and Prostate Cancer Progression. in Omega-3 Fatty Acids: Chemistry, Dietary Sources and Health Effects (Khan, W. ed.), Nova Science Publishers, Inc., Hauppauge, NY 11788 USA. 

 

  • “PTEN expression in breast cancer cells correlates with increased sensitivity to inhibitors of the PI3K pathway”. 92nd Annual Meeting of the American Association for Cancer Research, 689 (88), 2001.
  • “Akt Confers Resistance To Tamoxifen Inhibition Of Growth And Estrogen Receptor a Activity.” UT Health Science Center at San Antonio Department of Medicine 5th Annual Research Day. May 2002.
  • “The Role of the Akt Kinase Pathway in the Development of Hormone-Independent Breast Cancer”. Department of Medicine Research Conference. October 2002.
  • “Using Fatty Acids for the Treatment of Hormone Resistant Breast Cancer”, University of Texas at Austin, Division of Nutrition, Department of Human Ecology, January, 2004.
  • “The Role of the Akt Signaling Pathway in Hormone Resistance”. Department of Pediatrics Research Seminar Series, UTHSCSA, May 6, 2004.
  • “Akt and Hormone-Therapy Resistance”. University of Pittsburgh Cancer Institute, Division of Basic Research, January 4, 2005.
  • “Polyunsaturated Fatty Acids and Breast Cancer – Prevention and Treatment”. Aspen Cancer Conference, July 20, 2006
  • “Akt in Breast Cancer Carcinogenesis – Novel Pathways for Progression and Metastasis”. Department of Medicine Research Conference. January 2007
  • “Intracellular Signal Transduction Pathway Proteins As Targets for Cancer Therapy”. Texas State University, Department of Biochemistry, April 2007
  • “Targeting the Akt Pathway to Reverse Hormone Therapy Resistance”, Cotton Norris Cancer Center, Dartmouth University, June 2007
  • “Using Dietary Interventions to Reverse Akt-Mediated Resistance”, University of Texas at Austin, Department of Human Ecology, Division of Nutrition, September 2007
  • “Diet, Lifestyle and Cancer Progression: Making the Molecular Connections”, Keynote presentation for the 2nd Annual Cancer Symposium, University of Central Arkansas, March 2009
  • “Cancer and Diet: Charlie Tuna vs. Elsie the Cow”, Public presentation for the 2nd Annual Cancer Symposium, University of Central Arkansas, March 2009
  • In Vitro Modeling of the Molecular Effects Induced by Obesity in Prostate Cancer Cells”, Cancer Treatment and Research Center at UTHSCSA Cancer Prevention Retreat, UT Health Science Center at San Antonio, August 2009
  • “Using Omega-3 Fatty Acids to Modulate Prostate Cancer Progression”, The Office of Cancer Complementary and Alternative Medicine (OCCAM) of the National Cancer Institute, January 2011
  • “Obesity and Diet: Their Impact on Breast Cancer Progression and Outcome”, The University of Kansas Cancer Center, May 2011
  • “Modulation of Tumor Growth for Breast and Prostate Cancer: What His Greek Grandmother Taught Dr. Oz”, UT Forum, April 2013
  • “Health Effects of Wine – What Dr. Oz Learned from his Greek Grandmother”  UT Nutrition Institute, May 2013
  • “Obesity and Cancer – the Role of Inflammatory Pathways”, The Oswald T. Avery (Colgate 1900) Lecture, Colgate University, NY April 2014
  • “Dietary and Lifestyle Modulation of Cancer Tumor Growth : What Dr. Oz Learned from His Greek Grandmother”, Women’s Club of Greater Lakeway, April 2014

 

NTR 365 Nutrition and Genes

NTR 390 Molecular Nutrition