David A. Foster
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Professor of Biology and
Biochemistry |
Education:
A.B. 1976
University of California, Berkeley
Ph.D. 1982 Columbia University
Postdoc 1982-86 The Rockefeller University
Research Interests:
Cancer
Biology
The
goal of our research effort is to understand the biology of cancer cells. From an understanding of the defects in
a cancer cell, rational strategies for treatment can be developed. The progression from a normal cell that
is responsive to its environment, to a tumor cell that proliferates
uncontrollably, requires several genetic alterations to overcome built in
protections against unwanted cell proliferation and cancer. Perhaps the most important protection
against cancer is a program for cell suicide called apoptosis. Apoptosis is a default response to
excess DNA damage or inappropriate cell division 
signals.
To overcome the cells ability to commit suicide, cancer cells must acquire
mutations that result in the activation of what are known as “survival signals”
that suppress default apoptotic programs.
Survival signals in cancer cells are ideal targets for therapeutic
intervention because – in principle – suppression of survival results in
apoptosis. Our lab has been
working on survival signals generated by phospholipase D (PLD), an enzyme whose
metabolic product phosphatidic acid suppresses apoptosis induced by both DNA
damage and partial cell division signals.
Importantly, elevated PLD has been observed in several human cancers
including breast, gastric, colon, lung, pancreatic and renal cancer. Our recent work has indicated that
inhibiting the signals generated by PLD in breast cancer cells leads to
apoptosis, suggesting that PLD could be a good therapeutic target in cancers
where PLD signals are keeping the cancer cells alive. PLD and phosphatidic acid contribute to the activation of an
enzyme known as mTOR (the mammalian target of rapamycin), which has also been
implicated in cancer cell survival signaling. Importantly, mTOR can be targeted with rapamycin and
rapamycin induces apoptosis in human cancer cells that are surviving because of
their PLD activity. The lab is
currently trying to evaluate the potential for targeting PLD and mTOR in cancer
cells with elevated PLD activity.
The
lab is also investigating the role of another enzyme – protein kinase Cd (PKCd), which suppresses survival signaling and has been proposed to be a
tumor suppressor gene. PKCd
is also activated in response to apoptotic signals. Interestingly, the PKCd gene is localized to a region of chromosome 3p that
is frequently deleted in a variety of human cancers. Strategies for activating PKCd to induce apoptosis and suppress tumor growth are
being investigated.
Selected
Publications :
Lu, Z., Hornia, A.,Joseph,
T., Sukezane, T., Frankel, P., Zhong, M., Bychenok, S., Xu, L. Feig, L.A., and
Foster, D.A. (2000). Phospholipase D and RalA cooperate with the EGF receptor
to transform 3Y1 rat fibroblasts. Mol. Cell. Biol. 20, 462-467.
Shen, Y., Xu, L., and
Foster, D.A. (2001). Role for phospholipase D in receptor-mediated endocytosis.
Mol. Cell. Biol. 21,
595-602.
Zhong, M., Lu, Z., and
Foster, D.A. (2002). Downregulating PKC d provides a PI3K/Akt-independent survival signal that overcomes
apoptotic signals generated by c-Src overexpression. Oncogene 21,
1071-1078.
Joseph, T., Bryant, A., Wooden, R., Kerkhoff, E.,
Rapp, U.R. and Foster, D.A. (2002). Phospholipase D overcomes cell cycle arrest
induced by high-intensity Raf signaling. Oncogene 21, 3651-3658.
Xu, L., Frankel, P.,
Jackson, D., Rotunda, T., DSouza-Schorey, C., and Foster, D.A. (2003). Elevated
phospholipase D activity in H-Ras-, but not K-Ras-transformed cells by the
synergistic action of RalA and Arf6. Mol. Cell. Biol.
23, 645-654.
Chen, Y., Zheng, Y., and
Foster, D.A. (2003) Phospholipase D confers rapamycin resistance in human
breast cancer cells. Oncogene. 22, 3937-3942.
Foster, D.A. and Xu, L.
(2003). Phospholipase D in cell proliferation and cancer. Mol. Cancer Res. 1,
789-800.
Jackson, D., and Foster,
D.A. (2004). The enigmatic protein kinase C d: Complex roles in cell proliferation and survival. FASEB J. 18, 627-636.
Abbas, T., White, D., Hui,
L., Foster, D.A. and Jill Bargonetti, J. (2004). Inhibition of p53
transcription by down-regulation of protein kinase C d. J. Biol. Chem. 279, 9970-9977.
Hui, L. Abbas, T., Pielak,
R., Bargonetti, J. and Foster, D.A. (2004). Phospholipase D elevates the level
of MDM2 and suppresses DNA damage-induced increases in p53. Mol. Cell. Biol. 24, 5677-5686.
Foster, D.A. (2004).
Targeting mTOR-mediated survival signals in anticancer therapeutic
strategies. Exp. Rev. Anticancer Ther. 4, 691-701.
Chen, Y., Rodrik, V. and
Foster, D.A. (2005). Alternative phospholipase D / mTOR survival signal in
human breast cancer cells. Oncogene 24, 672-679.
Jackson, D., Zheng,
Y., Lyo, D., Shen, Y., Nakayama, K., Nakayama, K.I., Humphries, M., Reyland,
M.E., and Foster, D.A. (2005).
Suppression of cell migration by protein kinase Cd. Oncogene.
24, 3067-3072.
Rodrik, V., Zheng,
Y., Harrow, F., Chen, Y., and Foster, D.A. (2005). Survival signals generated
by estrogen and phospholipase D in MCF-7 breast cancer cells are dependent on
Myc. Mol. Cell. Biol.
25, 7917-7925.
Hui, L., Rodrik,
V., Pielak, R.M., Zheng, Y., and Foster, D.A. (2005). mTOR-dependent
suppression of protein phosphatase 2A is critical for phospholipase D survival
signals in human breast cancer cells. J. Biol.
Chem. 280, 35829-35835.
Zheng, Y.,
Rodrik, V., Toschi, A., Shi, M., Hui. L., Shen, Y., and Foster, D.A. (2006).
Phospholipase D couples survival and migration signals in response to stress in
human breast cancer cells. J. Biol. Chem. 281,
15862-15868.
Foster,
D.A. (2006). Phospholipase D survival signals as a therapeutic target in
cancer. Current
Signal Transduction Ther. 1, 295-303.
Rodrik, V.,
Gomes, E., Hui, L., Rockwell, P., and Foster, D.A. (2006). Myc stabilization in response to estrogen
and phospholipase D in MCF-7 breast cancer cells. FEBS
Lett. 580, 5647-5652.
Hui, L., Zheng, Y., Yan, Y., Bargonetti, J.,
and Foster, D.A. (2006). Mutant p53 in MDA-MB-231 breast cancer cells is
stabilized by elevated phospholipase D activity and contributes to survival
signals generated by phospholipase D. Oncogene 25, 7305-7310.
Foster, D.A. (2007). Regulation of mTOR by
phosphatidic acid? Cancer Res. 67, 1-4.