SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

T U M O R C E L L B I O L O G Y P R O G R A M
AYMEE PEREZ, PH.D.
Assistant Professor of
Cell Biology and Anatomy
DESCRIPTION OF RESEARCH
Sialomucin complex (SMC/Muc4) is a
heterodimeric glycoprotein complex consisting
of a mucin subunit ascites sialoglycoprotein-1
(ASGP-1) and a transmembrane subunit (ASGP-
2), which is aberrantly expressed on the surface of
a variety of tumor cells. Muc4 is transcribed from
a single gene, translated into a large polypeptide
precursor, and further processed to yield the mature
ASGP-1/ASGP-2 complex. Muc4 has complex
spatial and temporal expression patterns in
the normal rat, suggesting that it has complex
regulatory mechanisms.
Muc4 is expressed in most vulnerable epithelia
and is presumed to serve as a protective agent
whose mucin subunit provides a steric block to
the access of noxious agents such as bacteria or
viruses. In many of these epithelia, such as the
airway and cervix/vagina, Muc4 is constitutively
expressed. Two notable exceptions are the mammary
gland and uterus. In the uterus, Muc4 is
expressed in the virgin animal, but down-regulated
hormonally at the transcript level to repress
Muc4 expression at the time of blastocyst implantation.
Regulation in the mammary gland is
even more complex and includes transcriptional
and post-transcriptional levels of regulation.
Dr. Perez has two ongoing projects in her
laboratory. The first project investigates the
mechanisms involved in the transcriptional regulation
of Muc4 by prolactin and the transcription
factor PEA3. The second project focuses on the
post-transcriptional regulatory mechanisms involved
in repressing Muc4 in the virgin animal,
which are overridden during mid-pregnancy and
tumor progression. Dr. Perez and her colleagues
believe that these regulatory mechanisms provide
a key to understanding the function of Muc4 in
both the normal gland and its tumors.
SELECTED PUBLICATIONS
2002
Carraway, KL, Perez, A, Idris, N, Jepson, S,
Arango, M, Komatsu, M, Haq, B, Price-Schiavi,
SA, Zhang, J, and Carraway, CA. Muc4/
sialomucin complex, the intramembrane ErbB2
ligand, in cancer and epithelia: to protect and to
survive. Progress in Nucleic Acid Research and
Molecular Biology 71:149-85, 2002.
2003
Perez, A, Barco, R, Fernandez, I, Price-Schiavi,
SA, and Carraway, KL. PEA3 transactivates the
Muc4/Sialomucin Complex promoter in mammary
epithelial and tumor cells. Journal of Biological
Chemistry 278:36942-52, 2003.
HIGHLIGHTS/DISCOVERIES
• Demonstrated that up-regulation of the Muc4
gene in the 13762 sublines of the rat mammary
adenocarcinoma correlates with the overexpression
of transcription factor PEA3 and the receptor
tyrosine kinase ErbB2. PEA3 is capable of
transactivating the Muc4 promoter in a dosedependent
manner via direct attachment to a
PEA3 binding site. Ras and MEKK1 kinases
potentiate transcriptional activation of Muc4 by
PEA3. These data suggest that expression of
PEA3 in mammary tumors leads to up-regulation
of MUC4 transcription, the gene product
of which may contribute to the metastatic
potential of mammary tumors.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 91