ROLE OF A NEW PROTO-ONCOGENE,INT-5,IN BREAST NEOPLASIA

Project: Research project

Project Details

Description

Breast cancer is one of the most problematic types of human cancer. The
etiology of breast cancer involves a complex interplay of genetic,
hormonal, and dietary factors. Attempts to gain a clear understanding of
how these factors participate in mammary tumorigenesis have been hampered,
in part, by a lack of information on the specific genetic lesions that
contribute to the initiation and/or evolution of tumor development. Our
recent studies have resulted in identifying and cloning int-5 genomic DNA,
a unique and highly conserved novel mouse mammary tumor virus (MMTV)
integration locus gene from the BALB/c precancerous D2 hyperplastic
alveolar nodule(HAN). Int-5 is different from other int genes: it has been
found in precancerous, rather than cancerous neoplasms; it has been found
in chemically-, rather than virus-induced neoplasms; and it is expressed
in a variety of normal tissues, including the mammary gland. Int-5 is also
different from other oncogenes implicated in breast cancer (c-myc,
c-Ha-ras, c-erbB and HER-2/neu) because of its possible role in early
preneoplastic changes. Overexpression of int-5 in mammary and breast
tumors and also in breast cancer cell lines suggests its involvement in
mammary carcinogenesis. Therefore, int-5 gene is a good candidate for
investigating the role of this gene in mammary cancer. Our objective is
to test the transforming ability of int-5 gene directly to establish its
role in breast cancer using in vitro cell culture and in vivo transgenic
animal models. Our specific aims are: We will 1) clone mouse and human
int-5 cDNAs using mouse genomic probe and characterize these clones by
determining their nucleotide sequence; 2) determine the nucleotide sequence
and structural organization of int-5 genomic clone; 3) establish the
transforming ability of int-5 gene using MMTV-int-5 expression vector in
cell culture and transgenic animal model systems; transform normal human
breast epithelial cells (MCF-10) with MMTV-int-5 fusion gene and examine
whether overexpression of this gene in transformed cells leads to tumor
formation in nude mice. Also, we will generate int-5 transgenic animals,
examine these animals during different stages of mammary gland development
and pregnancy/lactation for formation of HAN and their progression to
mammary tumors, as well as examine any increased incidence of mammary
cancer in these animals; 4) establish the prognostic significance of int-5
overexpression by analyzing primary breast tumors for int-5 overexpression
and comparing these data with other clinical factors. These studies will
provide basic knowledge and help in understanding the characteristics of
int-5 gene and its encoded protein, as well as the transforming ability of
int-5 gene and its role in breast cancer. Transgenic animals also provide
a model to study the incidence of breast cancer, to determine how this
incidence can be reduced by various interventions, and to study the
synergistic effect of other oncogenes, if any, in the activation of this
gene in mammary neoplasms.
StatusFinished
Effective start/end date8/1/925/31/98

Funding

  • National Institutes of Health
  • National Institutes of Health: $103,699.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $105,125.00

ASJC

  • Medicine(all)

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