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.
SAN ANTONIO--Hormone responsiveness is one of the few prognostic markersfor breast cancer that actually predicts a better prognosis, Benita S.Katzenellenbogen, PhD, said in her William L. McGuire Memorial Lectureat 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%,"she said.
Dr. Katzenellenbogen, professor of cell and structural biology, Universityof Illinois College of Medicine, Urbana, cited two important aspects ofantiestrogen research and breast cancer that are of considerable interestboth in the pharmaceutical industry and research labs.
One is the possibility of developing antiestrogens that will show greatertissue selectivity. "In other words," she said, "agentsthat would be good antagonists at the breast and also at the uterus buthave estrogen-like agonistic activity in bone so as to maintain bone andalso provide good cardiovascular benefit."
There is already evidence that changing the chemical structure of antiestro-genscan facilitate some of these tissue-selective actions, she added.
Other research is aimed at understanding the mechanisms of resistanceto antiestrogens and developing methods to either overcome or prolong theperiod of time before resistance develops.
"Much of my own research, then, focuses on trying to understandhow anties-trogens like tamoxifen are effective in breast cancer,"Dr. Katzenellenbogen said, "and what changes occur in breast cancercells that make them become resistant to the beneficial effects of tamoxifen."
She noted that the response of genes to estrogens and antiestrogensdepends on four factors: the nature of the estrogen receptor (wild typeor variant); the nature of the gene promotor; the cell context (mammarygland or a uterine cell); and the nature of the ligand (an estrogen oran antiestrogen).
Furthermore, this gene response to estrogens and antiestrogens can bemodulated by cyclic AMP, growth factors, and agents that affect proteinkinases and cell phosphorylation pathways. "And these may accountvery importantly for the differences seen in the relative agonism and antagonismof agents like tamoxifen in different target cells," she said.
Women who respond to tamoxifen almost invariably progress to a statewhere they no longer benefit from the agent, she said, and the cause ismultifactorial.
Resistance can stem from changes in the estrogen receptor itself (mutations,deletions, etc). "Mutations in specific regions of the receptor canimpact 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 changesthat can lead to resistance involve post-receptor pathways, including changesaffecting phosphorylation, co-regulators, and the production of, and cellresponsiveness to, growth-stimulatory factors, such as TGF-alpha, and growth-inhibitoryfactors, such as TGF-beta.
Because of the effects of antiestrogens on growth factors, Dr. Katzenellenbogenand her colleagues asked whether a tamoxifen-resistant breast cancer cellline (developed in her lab) would likewise be resistant to added TGF-beta.
"We had suspected that since tamoxi-fen often increases TGF-betalevels (thus inhibiting cell growth), these tamoxifen-resistant cells mightnow be producing elevated levels of TGF-beta, and, in fact, we found thatthey are."
So despite elevated TGF-beta levels, these tamoxifen-resistant cellsgrow rapidly and no longer have their growth suppressed by antiestrogensor by additional TGF-beta, either added in the lab or produced by the cellsthemselves. "In this model of antiestrogen resistance," she said,"these cells show a loss of growth inhibition and, in fact, are nowweakly stimulated by tamoxifen, instead of being fully suppressed by it."