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Gordon B. Mills, M.D., Ph.D.
Our research program aims to identify the mechanisms by which normal cells (lymphocytes) and tumor cells (ovarian and breast cancer) perceive and respond to their environment. In particular, we are investigating the signaling mechanisms utilized by the T-cell receptor CD28 and interleukin-2 receptor (IL-2R) in lymphocytes. During this process, we have cloned a number of different tyrosine kinases and are utilizing molecular mutagenesis and biochemical techniques to determine their mechanism of action. One of these unique kinases (EMT/ITK) is a major signaling molecule in T-cell activation; the other (TTK) plays a role in cell-cycle progression, particularly during the G2/M transition. We demonstrated that mice that lack the SHP-1 tyrosine phosphatase have a greatly elevated propensity to develop leukemias, lymphomas, and breast cancer. Further, the recently identified phosphatase tumor suppressor gene MMAC1 is deleted or mutated in a number of leukemias and T-cell lines. Strikingly, EMT, SHP-1, and MMAC1 all regulate signaling through a PI-3K pathway. The mission of the laboratory is to understand the mechanisms by which signal transduction is linked to proliferation, invasion, and programmed cell death in T lymphocytes and in breast and ovarian cancer.

We recently identified a unique phospholipid growth factor, OCAF, in the ascites of ovarian cancer patients. OCAF, which is composed of a number of forms of lysophosphatidic acid, is the most potent growth factor yet identified for ovarian and breast cancer cells. We demonstrated that OCAF increases cell proliferation, increases invasion, and alters drug-induced programmed cell death, all of which suggests that it may play a role in the prognosis of a variety of cancers. We identified drugs that alter the production and function of this factor through its specific cell-surface receptor. Remarkably, OCAF levels are elevated in patients with early ovarian cancer, making this a potential new screening method for cancer. We will explore the role of OCAF in early diagnosis, establishment of prognosis, monitoring of therapy, and therapy of breast and ovarian cancer patients.

IL-2 and a number of cytokines and growth factors increase cell survival. These effects could either be direct or result from collaboration with other factors in the extracellular milieu. Strikingly, in the absence of serum, IL-2, IL-3, fibroblast growth factor, and epidermal growth factor all induce accelerated apoptosis. This is caused by the induction of the pro-apoptotic mediators BAX and myc by cytokines in the absence of induction of protective members of the BCL2 family.

The function of the recently cloned MMAC1/PTEN tumor suppressor was unknown. We have shown that MMAC1 specifically decreases signaling through the PI-3K pathway by a number of different mechanisms. This leads to increased rates of anoikis and programmed cell death, suggesting that MMAC1 acts as a tumor suppressor by promoting apoptosis and may participate in metastasis.

Selected Publications:
  1. Fang XJ, Gibson S, Flowers M, Furui T, Bast RC, Mills GB. Lysophosphatidylcholine stimulates AP-1 and the c-Jun N-terminal kinase activity. J Biol Chem 272:13683-13689, 1997
  2. Fang X-J, Jin X, Xu H-J, Liu L, Hogg D, Roth JA, Yu J, Xu F, Bast RC, Mills GB. Expression of P16 induces transcriptional down regulation of the RB gene. Oncogene 16:1-8, 1998
  3. Frankel A, Mills GB. Peptide and lipid growth factors decrease cisplatin-induced cell death in human ovarian cancer cells. Clin Cancer Res 2:1307-1313, 1996
  4. Gibson S, Truitt K, Lu Y, LaPushin R, Khan H, Imboden J, Mills GB. Efficient CD28 signaling leads to increases in the kinase activities of the TEC family tyrosine kinase EMT/ITK and SRC family tyrosine kinase LCK. Biochem J 330:1123-1128, 1998
  5. Shi Y, Wang R, Sharma A, Gao C, Wasfy G, Collins M, Penn L, Mills GB. Dissociation of cytokine signals for proliferation and apoptosis. J Immunol 159:5318-5328, 1997