Insulin-like Growth Factor-I Receptor: Molecular Biology, Pathophysiology, and
Therapeutic Opportunities
The insulin-like growth factors (IGFs) are a family of mitogenic polypeptides with important roles in normal growth
and development. The biological actions of the IGFs are mediated by the IGF-I receptor (IGF-IR), a transmembrane
tyrosine kinase that is structurally related to the insulin receptor. In addition to its basic requirement for cell cycle
progression, the IGF-IR plays a pivotal role in malignant transformation. The receptor is highly expressed in most
tumors and cancer cell lines where it functions as an antiapoptotic agent, conferring enhanced survival to malignant
cells. On the other hand, a decrease in the number of receptors was shown to cause massive apoptosis in several
transplantable tumors, suggesting that a critical determinant of tumor behavior is the concentration of cell-surface
receptors.
Current studies in my laboratory are aimed at elucidating the molecular mechanisms involved in transcriptional
regulation of the IGF-IR gene by a number of oncogenes and tumor suppressors. Since most neoplasias are
associated with activation of oncogenes or mutation of tumor suppressors, it is expected that our studies will shed
light on the interactions between these cellular factors in control of proliferation in normal and malignant states.
Specifically, we are focusing our research on two malignancies in which the involvement of the IGF-IR has been
well established: solid pediatric tumors and breast cancer. As described below in more detail, the transcription
factors involved in each particular type of malignancy, as well as their mechanisms of action, are clearly distinct.
However, a novel paradigm of tumorigenesis is emerging that involves dysregulation of the IGF-IR gene as a key
step in cancer etiology.
The IGF-IR in pediatric oncology: WT1 is a cell-type specific transcription factor whose deletion or mutation has
been implicated in the etiology of Wilms' tumor (a pediatric kidney cancer) and related nephropathies. Using DNase
footprintings, band shift assays, and transient and stable transfections we have demonstrated that WT1 inhibits the
expression of the IGF-IR gene via a mechanism that involves binding of the zinc-finger domain of WT1 to multiple
cis-elements in the IGF-IR promoter region. The following Specific Aims are currently being addressed in my lab:
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Molecular interactions between WT1 and p53 in transcriptional regulation of the IGF-IR gene: Several lines of
evidence suggest that WT1 and p53 act in concert to control proliferation. Interactions between these
transcription factors are potentially very complex due to the presence of multiple molecular forms of WT1. Our
working hypothesis is that p53 and WT1 cooperate to stringently repress IGF-IR gene expression, and that
mutation of either WT1 or p53 may disrupt the interactions between both proteins and/or between the proteins
and the IGF-IR promoter region. Understanding the molecular basis for the interplay between wild-type and
mutant forms of WT1 and p53 will provide the foundation for future studies aimed at interrupting the IGF
growth loop.
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Regulation of the IGF-IR gene by disrupted transcription factors: Tumor specific chromosomal translocations
that disrupt the molecular architecture of transcription factors have emerged as a common theme in pediatric
oncogenesis. As a result of these rearrangements, chimeric proteins are generated that are composed of modules
derived from unrelated genes. Desmoplastic small round cell tumor (DSRCT) is a primitive tumor in children
that is characterized by the recurrent translocation t(1;22)(p13;q12) that fuses the N-terminal (activation)
domain of the Ewings' sarcoma gene, EWS, to the C-terminal (DNA binding) domain of WT1. This event
converts WT1 from a tumor suppressor into a potential oncogene, EWS-WT1. Our hypothesis is that the
mechanism of action of EWS-WT1 in DSRCT involves competition with wild-type WT1 protein (encoded by the
untranslocated allele) for binding to consensus elements in the IGF-IR promoter. Binding of the chimeric
protein prevents WT1 binding, thus abrogating the antiproliferative activity of the tumor suppressor. The
operative implication of our findings is that addition of exogenous WT1 may reverse the malignant phenotype
associated with the EWS-WT1 translocation.
The IGF-IR in breast cancer: The IGF-IR has an important role in breast tumorigenesis, as illustrated by the fact
that blockage of this receptor in breast cancer cell lines by specific antibodies significantly inhibited cell
proliferation. Furthermore, recent epidemiological data has been presented, showing a positive correlation between
circulating concentrations of IGF-I and risk of breast cancer. Thus, the relative risk of breast cancer in
premenopausal women was 4.6 in the upper tertile of IGF-I values (compared to individuals in the lower tertile), and
it increased to 7.3 when the values of IGF binding protein-3 were incorporated in the analysis. These results indicate
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that augmented activation of the IGF-IR by endocrine IGF-I may be a key step in breast cancer. The following
Specific Aim is currently being pursued:
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Transcriptional regulation of the IGF-IR gene by BRCA1: The breast cancer susceptibility gene, BRCA1, has
been demonstrated to function as a transcription factor with tumor suppressor activity. Because the IGF-IR gene
is overexpressed during the early stages of most breast cancers, we have postulated that its promoter region
may constitute a molecular target for BRCA1 in breast-derived cells. Consistent with this hypothesis we have
recently shown that wild-type BRCA1 was capable of suppressing the activity of the IGF-IR promoter in a
number of cell lines. The implication of these results is that, at least part of, the proapoptotic activity of BRCA1
can be due to its repression of the strongly antiapoptotic IGF-IR. Mutation of BRCA1 may result in
transcriptional derepression of the IGF-IR gene, with ensuing activation of the overexpressed receptor by
locally produced or circulating IGF-I. Current studies are addressing the mechanisms responsible for
transcriptional control of the IGF-IR gene by BRCA1. These studies include an analysis of the specific
interactions between wild-type and mutant forms of BRCA1 and transcription factor Sp1. Future studies are
intended to elucidate the physical and functional interplay between BRCA1 and p53 in transcriptional
regulation of the IGF-IR gene.
Long-term objectives: As outlined above, current efforts in my laboratory are aimed at elucidating the molecular
mechanisms responsible for the transcriptional regulation of the IGF-IR gene, as well as its aberrant dysregulation in
various malignancies. I expect that these studies will lead in the near future into two major avenues. On one hand,
our studies may shed light on the complexity of the signaling mechanisms that control gene expression under
physiological and pathological conditions. In particular, these studies may help to elucidate the nature of the
interplay between wild-type and mutant oncogenes and tumor suppressors in transcriptional control of the IGF-IR
gene, a gene whose activation is crucial for the development of a malignant phenotype. On the other hand, our
studies may provide the foundations for future projects aimed at targeting the IGF-IR as a therapeutic approach for
those malignancies in which the IGF system is involved.
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