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Mechanism of action on cancer cell proliferation
Estradiol has been tied to the development and progression of cancers such as breast cancer, ovarian cancer and endometrial cancer. Estradiol effects target tissues by interacting with two nuclear hormone receptors called estrogen receptor α (ERα) and estrogen receptor β (ERβ). One of the functions of these estrogen receptors is gene expression. Once the hormone binds to the estrogen receptors, the hormone-receptor complexes then bind to specific DNA sequences, possibly causing damage to the DNA and an increase in cell division and DNA replicaiton. Eukaryotic cells respond to damaged DNA by stimulating or impairing G1, S, or G2 phases of the cell cycle to initiate DNA repair. As a result, cellular transformation and cancer cell proliferation occurs.

Suppressing the estrogenic effects of estradiol
In order to prevent and treat estrogen-dependent cancers, estrogen activity must be blocked in the affected tissues without compromising its beneficial effects, such as female and male reproduction, on unaffected tissues. Estrogen receptor α (ERα) was found to promote proliferation of cancer cells whereas estrogen receptor β (ERβ) acts as a tumor suppressor. Researchers have experimented by exposing HeLa cervical cancer cells to flavonoids and antioxidants to explore their effects on ERβ to encourage it’s anti-estrogenic effect or to discourage ERα estrogenic effects. In one study, a flavonoid called naringenin was used for its disease preventing component. Researchers used HeLa cervical cancer cells and HepG2 liver cancer cell lines. The researchers used in vivo and in vitro exposure of the cancer cells to estradiol to explore the impairment effects of flavonoids on estradiol. When naringenin was introduced to these cancer cells, estradiol and naringenin compete to bind to ERα, with the preference being the flavonone. As the concentration of naringenin increases, the molar fraction of estradiol binding to ERα decreases, thus reducing its estrogenic effect of cancer cell proliferation and inducing proapoptosis, or programmed cell death. Naringenin was found to bind to ERβ with up to five times higher affinity when compared to ERα, therefore increasing the anti-estrogenic effect of ERβ. In another study, pomegranate extract was used for its antioxidant properties. HeLa cervical cancer cells and SKOV3 ovarian carcinoma were experimented upon. These cancer cells were treated with different concentrations of pomegranate extract, referred to as PME, to investigate whether pomegranate extract effects cancer cells. At low concentrations, pomegranate extract showed no stimulation, but at higher concentrations, PME showed a growth inhibitory effect on the cancer cells. Pomegranate extract binds to estrogen receptors, namely ERα, in a concentration-dependent manner and inhibited the binding of estradiol. This encouraged the antiproliferative activity of cancer cells and suppressed growth of the malignant cells. Although pomegranate extract suppressed the growth of cancer cells, the study did not mention whether or not pomegranate extract exposure to existing cancer cells induced apoptosis or necrosis.

Prospective research
Although naringenin and other flavonoids and antioxidants could be acquired by eating foods rich in those components or by taking dietary supplements, the ability of an individual to absorb and metabolize these food nutrients varies from person to person. Researchers suggest that the complex role of flavonoids and plant extracts should be studied further before including them in specific nutritional recommendations. However, the studies do suggest that regular consumption of naringenin may slow the rate that estradiol-dependent cancer proliferate and naringenin is an exceptional option as a chemopreventive agent in estradiol-dependent cancers. Since pomegranate extract is an ERα antagonist, researchers propose that pomegranate extract is a promising alternative in breast cancer therapy and may be a preventative of estrogen-dependent breast cancers. Researchers also propose that the increase tumor suppression due to the presence of ERβ may result in a more successful response to chemotherapy treatments.