SAN ANTONIO--Hormone responsiveness is one of the few prognostic markers
for breast cancer that actually predicts a better prognosis, Benita S.
Katzenellenbogen, PhD, said in her William L. McGuire Memorial Lecture
at the San Antonio Breast Cancer Symposium.
"When estrogen receptors (ERs) or progesterone receptors (PRs)
are lacking in breast cancer tumors, less than 5% of women respond to tamoxifen
[Nolva-dex]. When ER/PR levels are high, response can be as high as 75%,"
Dr. Katzenellenbogen, professor of cell and structural biology, University
of Illinois College of Medicine, Urbana, cited two important aspects of
antiestrogen research and breast cancer that are of considerable interest
both in the pharmaceutical industry and research labs.
One is the possibility of developing antiestrogens that will show greater
tissue selectivity. "In other words," she said, "agents
that would be good antagonists at the breast and also at the uterus but
have estrogen-like agonistic activity in bone so as to maintain bone and
also provide good cardiovascular benefit."
There is already evidence that changing the chemical structure of antiestro-gens
can facilitate some of these tissue-selective actions, she added.
Other research is aimed at understanding the mechanisms of resistance
to antiestrogens and developing methods to either overcome or prolong the
period of time before resistance develops.
"Much of my own research, then, focuses on trying to understand
how anties-trogens like tamoxifen are effective in breast cancer,"
Dr. Katzenellenbogen said, "and what changes occur in breast cancer
cells that make them become resistant to the beneficial effects of tamoxifen."
She noted that the response of genes to estrogens and antiestrogens
depends on four factors: the nature of the estrogen receptor (wild type
or variant); the nature of the gene promotor; the cell context (mammary
gland or a uterine cell); and the nature of the ligand (an estrogen or
Furthermore, this gene response to estrogens and antiestrogens can be
modulated by cyclic AMP, growth factors, and agents that affect protein
kinases and cell phosphorylation pathways. "And these may account
very importantly for the differences seen in the relative agonism and antagonism
of agents like tamoxifen in different target cells," she said.
Women who respond to tamoxifen almost invariably progress to a state
where they no longer benefit from the agent, she said, and the cause is
Resistance can stem from changes in the estrogen receptor itself (mutations,
deletions, etc). "Mutations in specific regions of the receptor can
impact tremendously on hormone binding of either estrogen or antiestrogen,
as well as receptor transcriptional activity," she said.
Changes in the receptor itself probably account for perhaps 20% to 30%
of the cases of tamoxifen resistance, she noted. Other important changes
that can lead to resistance involve post-receptor pathways, including changes
affecting phosphorylation, co-regulators, and the production of, and cell
responsiveness to, growth-stimulatory factors, such as TGF-alpha, and growth-inhibitory
factors, such as TGF-beta.
Because of the effects of antiestrogens on growth factors, Dr. Katzenellenbogen
and her colleagues asked whether a tamoxifen-resistant breast cancer cell
line (developed in her lab) would likewise be resistant to added TGF-beta.
"We had suspected that since tamoxi-fen often increases TGF-beta
levels (thus inhibiting cell growth), these tamoxifen-resistant cells might
now be producing elevated levels of TGF-beta, and, in fact, we found that
So despite elevated TGF-beta levels, these tamoxifen-resistant cells
grow rapidly and no longer have their growth suppressed by antiestrogens
or by additional TGF-beta, either added in the lab or produced by the cells
themselves. "In this model of antiestrogen resistance," she said,
"these cells show a loss of growth inhibition and, in fact, are now
weakly stimulated by tamoxifen, instead of being fully suppressed by it."