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(Drug information on progesterone) receptors (PRs) are lacking in breast cancer tumors, less than 5% of women respond to tamoxifen(Drug information on tamoxifen) [Nolva-dex]. When ER/PR levels are high, response can be as high as 75%," she said.
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(Drug information on 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 an antiestrogen).
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 multifactorial.
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 they are."
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."