# ROLE OF GONADAL STEROIDS IN HEPATOCARCINOGENESIS

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 1991 · $229,802

## Abstract

Our previous findings have shown that ethinyl estradiol (EE) is a strong
promoter of hepato-carcinogenesis. Our more recent mechanistic studies have
revealed that EE causes an increase in a serum hepatocyte growth factor,
possibly in the EGF family, and that EE pretreatment dramatically
potentiates the responsiveness of cultured hepatocytes to subsequent
treatment with EGF. In this application we propose to test the hypothesis
that EE acts as a co-mitogen on hepatocytes by enhancing their
responsiveness to a growth factor which works through the EGF receptor
pathway. We will focus on the events which occur after the addition of EGF
to EE pretreated cells which may contribute to the potentiation of EGF
responsiveness. The specific aims are: 1) to determine the mechanism of
potentiation of EGF responsiveness by EE in primary cultures of rat
hepatocytes. The 2- fold increase in hepatocyte EGF receptor levels induced
by EE may not be sufficient to account for the dramatic potentiation of
EGF-induced DNA synthesis. We plan to determine whether one or more of the
components of the EGF signal transduction pathway is affected by EE
pretreatment; 2) to develop a continuous liver cell culture model which
exhibits an EE-induced potentiation of EGF responsiveness in a manner
similar to that observed in primary hepatocytes. The development of this
model is desirable for studies on the effects of EE on EGF responsiveness
in initiated cells (see below). We will initially use the well
characterized WB liver cell line and determine whether these cells are
positive for estrogen receptors (estr). If not, we will introduce the estr
gene in an expression vector by transfection or by electroporation. We will
then characterize the response of these cells to EGF following EE
treatment; 3) to determine the effect of EE on EGF responsiveness in
initiated cells. We have shown in vivo that liver DNA synthesis in response
to EE is transient and returns to baseline levels even with continuous EE
treatment. However, in DEN treated rats, initiated hepatocytes must
continue to grow in order to give rise to preneoplastic foci. Here we will
focus on determining the mechanism(s) by which initiated cells are altered
in their growth response to the continuous presence of EE. We will initiate
EE/EGF responsive liver cell lines (see above) by transfection with
activated oncogenes under an inducible promoter (e.g. MT-ras, MT-myc and
MT-raf) and determining the effect of the expression of these genes on
EE/EGF responsiveness. We will also determine whether hepatocytes isolated
from GGT foci are altered in their responsiveness to EE/EGF compared to
normal hepatocytes; and 4) to characterize further the serum factor(s)
enhanced by E treatment in vivo initially by determining whether this
factor is novel or the same as HPTA, recently purified and characterized by
Michalopoulos and co-workers. These studies should provide new information
on the mechanisms of both liver growth stimulation and...

## Key facts

- **NIH application ID:** 3174286
- **Project number:** 5R01CA036701-08
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **SAM.gov UEI:** FTMTDMBR29C7
- **Principal Investigator:** JAMES Donald YAGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1991
- **Award amount:** $229,802
- **Award type:** 5
- **Project period:** 1984-01-01 → 1993-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3174286

## Citation

> US National Institutes of Health, RePORTER application 3174286, ROLE OF GONADAL STEROIDS IN HEPATOCARCINOGENESIS (5R01CA036701-08). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3174286. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*