tumor cell biology program - Sylvester Comprehensive Cancer Center

Qadan, LR, Perez-Stable, C,
Schwall, RH, Burnstein, KL, Ostenson,
RC, Howard, GA and Roos, BA. Hepatocyte
growth factor and vitamin D cooperatively
inhibit androgen-unresponsive
prostate cancer cell lines. Endocrinology
141:2567, 2000.
Grad, JM, Lyons, LS, Robins, D and
Burnstein, KL. The androgen receptor
(AR) amino-terminus imposes androgenspecific
regulation of AR gene expression
via an exonic enhancer. Endocrinology
142:1107, 2001.
Tekur, S, Lau, KM, Long, J,
Burnstein, KL and Ho, SM. Expression
of RFG/ELE1 alpha/ARA70 in normal
and malignant prostatic epithelial cell
cultures and lines: Regulation by methylation
and sex steroids. Molecular Carcinogenesis
30:1, 2001.
Schwartz, GG, Lokeshwar, BL,
Burnstein, KL. Correspondence re: S.
E. Blutt, T. C. Polek, L. V. Stewart, M.
W. Kattan, and N. L. Weigel, A Calcitriol
Analogue, EB1089, inhibits the growth
of LNCaP tumors in nude mice. Cancer
Research 61:4294, 2001.
HIGHLIGHTS/DISCOVERIES
• The identification of p21 and p27 as
the vitamin D targets involved in halting
the cell cycle predict that these cell
cycle regulators may serve as indicators
of vitamin D sensitivity in prostate cancer
biopsies. They found that the transcription
factor Myc cooperates with
AR in the regulation of AR mRNA.
This finding suggests that Myc may
play a role in dictating androgen sensitivity
and androgen-mediated cell proliferation.
Since the Myc gene is often
amplified in advanced prostate cancer,
there may be a link between AR and
Myc in tumor progression.
Kermit L. Carraway, Ph.D.
Professor of Cell Biology
and Anatomy
DESCRIPTION OF RESEARCH
For much of the past decade, Dr.
Carraway’s primary research effort
has been concerned with the role of cell
surface glycoproteins in mammary cancer,
focusing on a particular glycoprotein
complex (sialomucin complex, SMC, rat
Muc4) that his laboratory discovered
about 20 years ago. This complex
has both mucin- and growth factorcontaining
subunits. This putative
bifunctionality can potentially contribute
to two of the major attributes of
cancer cells, loss of adhesiveness, and autonomous
growth. It has been implicated
in metastasis. The anti-adhesive function
of SMC allows it to block tumor cell killing
by lymphokine-activated killer cells,
a mechanism, which permits the SMCoverexpressing
tumor cells to escape immune
surveillance. One of the two
growth factor domains of the transmembrane
subunit of SMC has been shown
to act as an intramembrane ligand for
the class I tyrosine kinase growth factor
receptor ErbB2/HER2/Neu. Binding of
SMC as a ligand to ErbB2 potentiates
tyrosine phosphorylation of the receptor
and its co-receptor ErbB3, when the
latter is stimulated with its soluble ligand
Neuregulin.
His team is currently investigating
the effects of this receptor modulation
on downstream signaling pathways and
cellular functions. Recently, they have
found that induction of SMC overexpression
in a melanoma tumor cell model
potentiates both primary tumor growth
and metastasis when the tumors are injected
into nude mice. The former is correlated
with a reduction in apoptosis in
the SMC-overexpressing animals. One
important question is whether the antiapoptotic
effects of SMC result from its
growth factor domains or other features
of its structure. Since SMC has been
implicated in breast cancer progression,
it is of interest to know how it is regulated
in mammary gland. Investigations
of primary mammary epithelial cells indicate
a major role for post-transcriptional
regulation. Interactions with the
extracellular matrix regulate SMC expression
at the translational level, while transforming
growth factor-beta regulates it
at the post-translational level. Both of
these types of regulation are lost in rat
mammary tumor cells, and both are
known to change during human breast
cancer progression. These and other results
suggest that MUC4 acts as a “tumor
progressor” gene rather than a
primary oncogene; thus, SMC might
serve as a target for prognosis and therapies
in breast cancer.
PUBLICATIONS
Komatsu, M, Yee, L and Carraway,
KL. Overexpression of sialomucin complex,
a rat homolog of MUC4, inhibits
tumor killing by lymphokine-activated
killer cells. Cancer Research 59:2229,
1999.
Carraway, KL III, Rossi, EA,
Komatsu, M, Price-Schiavi, SA, Huang,
D, Guy, PM, Carvajal, ME, Fregien, N,
Carraway, CAC and Carraway, KL. An
intramembrane modulator of the ErbB2
receptor tyrosine kinase that potentiates
neuregulin signaling. Journal of Biological
Chemistry 274:5263, 1999.
Huang, J, Zhang, B-T, Li, Y, Mayer,
B, Carraway, KL and Carraway, CAC.
c-Src association with and phosphorylation
of p58 gag , a membrane- and
microfilament-associated retroviral gaglike
protein in a xenotransplantable rat
mammary tumor. Oncogene 18:4099,
1999.
Carraway, CAC, Carvajal, ME and
Carraway, KL. Association of the Ras/
MAP kinase signal transduction pathway
with microfilaments. Evidence for a
p185neu-containing cell surface signal
transduction particle. Journal of Biological
Chemistry 274:25659, 1999.
Li, Y, Carraway, KL and Carraway,
CAC. Molecular associations of the core
glycoprotein complex from a microfilament-associated
signal transduction par-
4
UM/Sylvester Comprehensive Cancer Center Scientific Report 2002