Dr. Jackson received his BS in zoology from the University of Texas, Austin, and then worked in the laboratories of Douglas Yee, MD, and Michael Brattain, PhD, on growth factor signal transduction in breast and colon cancer at the University of Texas Health Science Center at San Antonio. These studies resulted in 20 publications, including 7 as first author. For his PhD research at the University of Texas Health Science Center at San Antonio (mentor: Olivia Pereira-Smith, PhD), he published studies describing the chromatin modifications that drive cellular senescence in both normal human fibroblasts and in breast cancer cell lines treated with DNA damaging chemotherapy. This work was funded by the Department of Defense Breast Cancer Research Program (DoD BCRP). For his postdoctoral fellowship, he extended this work into mouse models of breast cancer at MD Anderson Cancer Center in the laboratory of Gigi Lozano, PhD. Using transgenic and knockin mouse models, he showed that p53 mutant mammary tumors responded better to chemotherapy than p53 wild type tumors, and he defined the mechanism for these responses (Jackson JG et al, 2012, Cancer Cell, 21(6):793-806). p53 wild type tumors enter a growth arrested, senescent state and express many cytokines and chemokines that can drive relapse. p53 mutant tumors, however, fail to arrest, continuing through the cell cycle with DNA damage resulting in mitotic catastrophe, apoptosis and cell death. These findings support and provide mechanism for some retrospective clinical studies that showed p53 mutant breast tumors have a much higher probability of achieving a complete pathological response following chemotherapy treatment than p53 wild type tumors. Taken together, these studies provide a basis for reevaluating the paradigm for p53 in cancer therapy. Cancer Cell featured this study on its cover, and it was also featured in Nature as a “Community Choice, The most viewed papers in science;” Cancer Research “Highlights,” Breast Cancer Research “Viewpoint,” and also Oncotarget “Research Perspectives.” It was recommended by The Faculty of 1000 as an “Exceptional” article (the highest ranking), was selected as a “Breakthrough of the Year” in breast cancer research at the 2012 AACR San Antonio Breast Cancer Symposium, and was honored as the “Outstanding Research Publication Award supported by The Ernst W. Bertner Memorial Fund” for MD Anderson Cancer Center for 2012. At AACR 2013, it was featured in the “Best of Cancer Cell 2012” special issue and was again chosen as a cover subject. The project was funded by an Odyssey Scholarship at MD Anderson. In 2015, Dr. Jackson joined the faculty in the Biochemistry Department at Tulane School of Medicine. Ongoing studies in his lab are examining the role of senescence in driving relapse and whether eradicating senescent cells can improve response to chemotherapy. These studies are currently funded by a DoD BCRP Breakthrough Award.
The Jackson Laboratory investigates the response of breast cancer to therapeutics, and why some tumors respond well and others poorly.
In breast and many other solid tumor types, residual tumor is still present at the time of surgery following chemotherapy treatment. Our lab previously showed that the tumor suppressor p53 is paradoxically associated with poor responses to chemotherapy treatment in breast cancer. p53, 'the guardian of the genome', is a transcription factor that is activated in response to cellular stressors and DNA damage, and initiates cell cycle arrest or apoptosis. p53 is mutated in ~30% of breast tumors.
We found that in treated breast tumors, p53 directs tumor cells to growth arrest and senescence preferentially over apoptosis. These senescent cells persist and produce cytokines and chemokines that can support proliferation/survival, driving early relapse. p53 mutant tumors fail to arrest, continuing into mitosis with DNA damage, resulting in mitotic catastrophe, apoptosis and greater tumor regression.
Current investigations in the lab are centered on determining 1) the cell that causes relapse in a treated tumor; 2) how senescent cells contribute to relapse; 3) the molecular mechanisms driving proliferation in a relapsing tumor; 4) how much would response to chemotherapy be improved if senescent cells were eradicated. To answer these questions, we will use a combination of genetically engineered mouse models, ex vivo lentiviral gene transfer, in vivo gene expression analyses using fluorescent and luminescent markers, survival analyses and molecular and cellular techniques.
Breast cancer tumorigenesis and drug response, cellular senescence, mouse models, mouse genetics, tumor suppressor mechanism of action, p53
Cellular senescence, including mechanisms of induction, chromatin changes and consequences to organisms.
Jackson JG, White MF, Yee D. Insulin receptor substrate-1 (IRS-1) is the predominant signaling molecule activated by insulin-like growth factor-I (IGF-I), insulin, and interleukin-4 (IL-4) in estrogen receptor positive human breast cancer cells. J Biol Chem 1998 Apr. 17; 273 (16): 9994-10003.
Lee AV¥, Jackson JG¥, Gooch JL, Hilsenbeck SG, Coronado-Heinsohn E, Osborne CK, Yee D. Enhancement of the insulin-like growth factor signaling pathway by estrogen in human breast cancer. Mol Endo 13: 787-796, 1999 ¥These authors contributed equally to this work.
Jackson JG, Yoneda T, Clark GM and Yee D. Elevated levels of p66 Shc are found in breast cancer cell lines and primary tumors with high metastatic potential. Clin Cancer Res 6:1135-1139, 2000.
Jackson JG, Kreisberg JI, Koterba AP, Yee D and Brattain MG. Phosphorylation and Nuclear Exclusion of the Forkhead Transcription Factor FKHR after Epidermal Growth Factor Treatment in Human Breast Cancer Cells. Oncogene: 19(40): 4574-4581, 2000
Jackson JG, Zhang X, Yoneda T, Yee D. Regulation of breast cancer cell motility by insulin receptor substrate-2 (IRS-2) in metastatic variants of human breast cancer cell lines. Oncogene: 20(50): 7318-25, 2001 Nov 1
Jackson JG, St. Clair P, Sliwkowski MX and Brattain MG. Blockade of EGF or Heregulin Dependent ErbB2 Activation with the Anti-ErbB2 Monoclonal Antibody 2C4 has Divergent Downstream Signaling and Growth Effects. Cancer Res. 2004 Apr 1;64(7):2601-9.
Jackson JG and Pereira-Smith OM. Primary and Compensatory Roles for RB Family Members at Cell Cycle Gene Promoters that are Deacetylated and Downregulated in Doxorubicin Induced Senescence of Breast Cancer Cells. Mol Cell Biol. 2006 Apr; 26(7): 2501-2510.
Jackson JG and Pereira-Smith OM. p53 is preferentially recruited to the promoters of growth arrest genes p21 and GADD45 during replicative senescence of normal human fibroblasts. Cancer Res: 66(17) 8356-60, Sept. 1, 2006 PRIORITY REPORT.
Post SM, Quintás-Cardama A, Pant V, Iwakuma T, Hamir A, Jackson JG, Maccio DR, Bond GL, Johnson DG, Levine AJ, Lozano G A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. Cancer Cell. 2010 Sep 14;18(3):220-30.
Jackson JG, Pant V, Li Q, Chang LL, Quintás-Cardama A, Garza D, Tavana O, Yang P, Manshouri T, Li Y, El-Naggar AK, Lozano G. p53 mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell, 2012 Jun 11;21(6):793-806 (Featured on cover)