Scientific rationale for postmenopause delay in the use of conjugated equine estrogens among postmenopausal women that causes reduction in breast cancer incidence and mortality

Abstract

High-dose synthetic estrogens were the first successful chemical therapy used in the treatment of metastatic breast cancer in postmenopausal women, and this approach became the standard of care in postmenopausal women with metastatic breast cancer between the 1950s and the end of the 1970s. The most recent analysis of the Women's Health Initiative estrogen-alone trial in hysterectomized women revealed a persistently significant decrease in the incidence of breast cancer and breast cancer mortality. Although estrogens are known to induce the proliferation of breast cancer cells, we have shown that physiologic concentrations induce apoptosis in breast cancer cells with long-term estrogen deprivation. We have developed laboratory models that illustrate the new biology of estrogen-induced apoptosis or growth to explain the effects of estrogen therapy. The key to the success of estrogen therapy lies in a sufficient period of withdrawal of physiologic estrogens (5-10 y) and the subsequent regrowth of nascent breast tumor cells that survive under estrogen-deprived conditions. These nascent tumors are now vulnerable to estrogen-induced apoptosis.

Figure 1. Structures of the estrogenic constituents of premarin

Estradiol, equilin, estrone and equilenin were used in our experimental studies.

Figure 2. Cell proliferation assay analysis of the biological properties of active steroids in CEE in breast cancer cells

(A) MCF7 cells were grown in E₂ stripped media for 3 days and treated for 7 days with various concentrations of E₂, equilin, estrone and equilenin and compared to the Veh (control). (B) Equilin, estrone and equilenin drastically inhibited the growth of MCF7:5C cells in a similar manner as E₂. The experiments were completed in triplicates and performed as previously described

Figure 3. Effects of estradiol and active estrogens in CEE on apoptosis in MCF7:5C cells

MCF7:5C cells were seeded in 100mm plates and treated with Veh (control), 1nM E₂, 1nM Equilin, 1nM estrone and 1uM equilenin for 72 hours and cells were stained with FITC-annexin V and propidium iodide and analyzed by flow cytometry and performed as previously described. The upper right box of vehicle treated (Veh) cells have low apoptotic cells (1.71%), whereas all for estrogens, this fraction is increased (circled upper right hand box).

Figure 4. The success of estrogen therapy is dependent on menopausal status of a woman

A. Treatment of women immediately after menopause with CEE results in sustained growth of nascent ER positive tumors, whereas treatment 5. years after menopause causes apoptotic cell death. B. Estrogen withdrawal in postmenopausal women causes ER positive dependent cells to die but some cells continue to grow independent of estrogen