# ROLE OF GONADAL STEROIDS IN HEPATOCARCINOGENESIS

> **NIH NIH R01** · DARTMOUTH COLLEGE · 1987 · $148,710

## Abstract

Work carried out in our laboratory and by others has clearly
demonstrated that the synthetic  estrogens mestranol and ethinyl
estgradiol (EE) promote hepatocarcino-genesis in rats and, we
have been conducting experiments designed to probe the
mechanisms of promotion by EE.   An initial response to EE
treatment in control rats is a significant increase in liver DNA
synthesis which ceases by 21 days despite continuous treatment
with the estrogen.  Studies in progress have shown that
hepatocyte growth factors appear in the serum and plasma of EE-
treated rats.  In vitro studies with cultured hepatocytes indicate
the EE alone does not stimulate DNA synthesis.  During
carcinogenesis in initiated animals, upon chronic treatment with
EE the initiated cells undergo clonal expansion to produce
preneoplastic foci.  Thus, it is likely that initiated hepatocytes
are altered in their sensitivity to growth stimulators and/or the
growth inhibitors involved in regulating normal hepatocyte growth
in the presence of chronic EE treatment.  We wish to begin to
focus our studies on the nature of the alterations in growth
regulation in the preneoplastic hepatocytes promoted by EE.  We,
therefore, wish to investigate the hypothesis that promotion by
EE stimulates or alters the production of growth factors found
both in the serum/plasma and in the hepatocytes themselves and
that preneoplastic hepatocytes are altered in their growth
responses to these factors.  The specific aims of this proposal are:
1. to characterize the growth factor(s) induced by treatment of
female rats with EE.  2.  to determine whether transforming
growth factor (TGF)-type alpha and beta growth factors are
present and increased or decreased in the livers of rats during
treatment with EE.  3. to determine whether isolated hepatocytes
from GGT foci are altered in their response to various growth
factors including those identified in Specific Aims 1 and 2 above.
4. to continue studies designed to determine whether the
elevation of hepatic bile acids caused by EE treatment has a
mechanistic role in promotion by EE.  5. to continue studies
designed to extend our initial observations that tamoxifen (T)
inhibits induction of liver DNA synthesis and promotion by EE but
alone has promoting activity.

## Key facts

- **NIH application ID:** 3174280
- **Project number:** 2R01CA036701-04A1
- **Recipient organization:** DARTMOUTH COLLEGE
- **SAM.gov UEI:** EB8ASJBCFER9
- **Principal Investigator:** JAMES Donald YAGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $148,710
- **Award type:** 2
- **Project period:** 1984-01-01 → 1990-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3174280

## Citation

> US National Institutes of Health, RePORTER application 3174280, ROLE OF GONADAL STEROIDS IN HEPATOCARCINOGENESIS (2R01CA036701-04A1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3174280. Licensed CC0.

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