SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M
SELECTED PUBLICATIONS
2002
Singal, R, vanWert, JM, and Ferdinand, L Jr.
Methylation of alpha-type embryonic globin gene
alpha pi represses transcription in primary erythroid
cells. Blood 100:4217-22, 2002.
Singal, R, Wang, SZ, Sargent, T, Zhu, SZ, and
Ginder, GD. Methylation of promoter proximal
transcribed sequences of an embryonic globin
gene inhibits transcription in primary erythroid
cells and promotes formation of a cell type-specific
methyl cytosine binding complex. Journal of
Biological Chemistry 277:1897-1905, 2002.
Noss, KR, Singal, R, and Grimes, SR. Methylation
state of the prostate specific membrane antigen
(PSMA) CpG island in prostate cancer cell
lines. Anticancer Research 22:1505-11, 2002.
2003
Yaturu, S, Harrara, E, Nopajaroonsri, C, Singal,
R, and Gill, S. Gynecomastia attributable to human
chorionic gonadotropin-secreting giant cell
carcinoma of lung. Endocrinology Practices
9:233-35, 2003.
JOYCE M. SLINGERLAND, M.D., PH.D.,
F.P.R.C.(C)
Professor of Medicine
DESCRIPTION OF RESEARCH
Dr. Slingerland’s research investigates how
cancers escape negative growth controls. Following
her discovery of a key inhibitor of cell
cycle progression, p27, Dr. Slingerland and her
colleagues went on to demonstrate that p27 levels
are reduced in up to 60 percent of common human
cancers (breast, prostate, lung, ovarian, and
others), in association with poor patient prognosis.
Dr. Slingerland showed that the therapeutic
effect of antiestrogens in breast cancer requires
the cyclin-dependent kinase (cdk) inhibitors p21
and p27 to mediate growth arrest. Oncogenic
activation of mitogenic signaling via the mitogenactivated
protein kinase (MAPK) pathway deregulates
p27 function, causing tamoxifen
resistance in breast cancer. She provided key insights
demonstrating the role of cell cycle inhibitors
p15 and p27 as mediators of G1 arrest by
transforming growth factor-beta (TGF-β) and
demonstrated that cancer cells lose responsiveness
to this growth inhibitory cytokine through loss or
deregulation of p27. In a recent publication, her
laboratory demonstrated that checkpoint loss
during cancer progression makes p27 an essential
mediator of arrest. They also showed that functional
inactivation of p27 in human cancers can
either occur through accelerated p27 degradation
or through altered p27 phosphorylation leading
to p27 mislocalization. The laboratory recently
showed that activation of mitogenic signaling via
the receptor tyrosine kinases and the phosphoinositol
3’ kinase pathway alters p27 phosphorylation
and function and the protein accumulates
in the cytoplasm away from its targets in the
nucleus. This work links oncogene activation
with loss or inactivation of the cell cycle inhibitor,
p27, elucidating a major mechanism of loss
of growth control in cancer progression.
Dr. Slingerland’s laboratory also is investigating
the cause of aggressive estrogen receptor negative
(ER-) breast cancers. Her group has found
that oncogenic receptor tyrosine kinase and cSrc
activation may not only activate mitogenic signaling
leading to aggressive proliferation, but also
lead to loss of detectable ER protein in ER negative
(ER-) breast cancers. One third of newly diagnosed
breast cancers are ER- and have a poor
prognosis. Investigation of the mechanisms underlying
the loss of ER expression showed that all
of 70 primary ER- breast cancers expressed ER
mRNA. Src or proteasome inhibition increased
ER levels, and Src transfection stimulated both
ligand activated ER transcriptional activity and
ER proteolysis. Cotransfection of Her2 and Src
reduced ER levels further. ER- primary breast
cancers and cell lines showed increased Src activity
compared to ER+ cancers and cell lines, and
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UM/Sylvester Comprehensive Cancer Center Scientific Report 2004