Paradoxic Actions of Estrogen in Breast Cancer

Armen Hareyan's picture

After an inauspicious start in the 1960s as failed investigational oral contraceptives, selective estrogen receptor modulators (SERMs) have had their day in the sun as agents for breast cancer treatment and chemoprevention. Now an additional benefit may be realized for SERMs and other antiestrogens: sensitizing breast cancer to estrogen and allowing the hormone to be used as third-line breast cancer therapy. The 2008 David A. Karnofsky Memorial Award recipient V. Craig Jordan, OBE, PhD, DSc, Vice President and Scientific Director for Medical Science at Fox Chase Cancer Center, described how his career traced the multifarious career of tamoxifen and raloxifene and contributed to advancing the knowledge of estrogen's paradoxic actions in breast cancer.

Long-term therapy with SERMs or aromatase inhibitors may diminish these agents' antitumor properties and may lead to a window for the potential use of estrogen to kill cancer cells. Studies in animal models indicate that long periods of estrogen deprivation, roughly equivalent to 5 years of antiestrogen treatment for estrogen receptor-positive breast cancer, can supersensitize cancer cells to estrogen. The hormone can then trigger apoptosis when it combines with its receptor on tumor cells. A clinical trial of estrogen involving patients whose disease has developed resistance to antihormone therapies has been planned and funded, said Dr. Jordan.

In the late 1960s, using hormones to treat cancer was not an option. Dr. Jordan's doctoral research involved an antiestrogen, ICI 46474, which prevented embryonal implantation in rats and had potential as a morning-after contraceptive pill. When the agent actually increased the rate of pregnancies in human clinical trials, further development as a contraceptive was dropped. Dr. Jordan obtained a supply of the compound to characterize its estrogen receptor binding; the antiestrogen eventually became tamoxifen.


Haddow's Paradox Describes Opposing Actions of Estrogen
Sir Alexander Haddow, FRS, delivered the first Karnofsky Lecture in 1970. His topic was the failure of cytotoxic chemotherapeutic agents to be more like antibiotics, with their specific targets, predictive tests for sensitivity, and high therapeutic success. The only "glimmer of light," according to Dr. Jordan, in Dr. Haddow's address was his observation, decades beforehand, that a group of synthetic nonsteroidal estrogens could produce tumor regression in animals. In clinical trials, these agents produced an "extraordinary regression" of breast cancer in humans -- but only in a few patients. "Large tumors would just melt away with high-dose estrogen," Dr. Jordan said. This finding was regarded as "monumental," but the mechanism remained unknown and interest faded.

Despite Dr. Haddow's grim assessment in the 1970s, the decade saw the evolution of tamoxifen as the first targeted therapy for breast cancer. The estrogen receptor, previously viewed only as a prognostic marker, became the first drug target. Knowledge of the complexity of SERM activity in different tissues and in the presence of coactivator and corepressor substances continues to evolve. Despite the development of aromatase inhibitors for breast cancer treatment, SERMs maintain their important public health role; when used to prevent osteoporosis, they reduce rates of breast cancer, and they have lipid-lowering effects.

Drug resistance remains a problem in antiestrogen therapy of breast cancer, Dr. Jordan said. After a long period of initial responsiveness to SERMs, estrogen receptor-positive tumors enter phase I resistance, in which growth is stimulated not only by SERMs but by estrogen as well. During this phase, the tumor continues to be responsive to aromatase inhibitor therapy. After approximately 5 years of treatment with tamoxifen, the entire configuration of the cancer cell changes drastically (phase II); growth is now stimulated by antiestrogens, but exposure to physiologic levels of estrogen causes cell death -- the explanation of Haddow's paradox. In experimental animals, dramatic regression of small tumors has been demonstrated with physiologic levels of estrogen given during phase II resistance to SERMs. Large tumors treated in this way recover their sensitivity to antihormone agents, which then appear to work when reintroduced.

This schema of sequential resistance and responsiveness underlies the clinical trial that is now going forward. The trial will enroll postmenopausal women with metastatic breast cancer who have first succeeded with and then lost their responsiveness to two consecutive antihormone therapies. Those who respond to 12 weeks of low-dose estrogen therapy -- an expected 30% based on observations of women given high-dose estrogen -- will receive an aromatase inhibitor to maintain tumor control. If three women out of 10 have a good response, the remaining seven can serve as a test population to identify other mechanisms that may be keeping those tumors from responding to estrogen, added Dr. Jordan.