Type II Estrogen Receptors

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One reason why phytoestrogens other than genistein may be less problematic is that they appear to inhibit cancer through additional estrogen-receptor-related means. Thus far we have discussed the effects of genistein and other phytoestrogens on what is called the classic estrogen receptor, or type I receptor. A second




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type has also been reported, the type II estrogen receptor; its existence is still somewhat controversial, since it has not yet been possible to purify its protein. Some researchers believe this will take place in the near future, however.59 Type II receptors apparently exist at a higher concentration on the nuclear surface than type I and have a lower affinity for estrogen. Type II receptors do not induce a classic estrogen response after activation and appear to have a different function.

A number of in-vitro studies have indicated that fla-vones and flavonols could inhibit cancer cell proliferation by binding to type II estrogen receptors. Apparently, type II estrogen receptors are overex-pressed in a wide range of human tumors, including breast, pancreatic, prostate, lymphatic, skin, ovarian, kidney, colon, and lung. Although type II receptors weakly bind estrogen, they more potently bind a compound identified as methyl-p-hydroxyphenyllactate (MeHPLA). Flavonoids and/or their metabolites mimic MeHPLA and bind to type II receptors, in competition with estrogen.60,61 Receptor binding with MeHPLA or flavonoids inhibits cell proliferation, whereas binding with estrogen stimulates it. For example, in some in-vitro studies luteolin and quercetin inhibited cancer cell proliferation by binding to type II receptors; in one, luteolin inhibited proliferation of human breast cancer cells at an IC50 of about 42 pM, reportedly by this mechanism.60,62 A number of other in-vitro studies have reported that quercetin (at about 10 mM) inhibited a wide variety of human tumor cell lines by affecting type II receptors.60,63-68

In addition to inhibiting cell proliferation by binding to type II receptors, flavones have prevented the overexpression of MeHPLA esterase by cancer cells; this enzyme degrades MeHPLA, thereby decreasing its growth-inhibitory effects. Oral administration of luteolin (at 56 mg/kg) in drinking water for seven days blocked estrogen stimulation of MeHPLA esterase in rat uterine tis-sues.61 The equivalent human dose is roughly 910 milligrams of luteolin per day. Similar results were seen after subcutaneous administration of luteolin in rats (at 5 mg/kg).69 The equivalent human oral dose is about 540 milligrams per day.

Flavones and flavonols (i.e., apigenin, luteolin, and quercetin) may inhibit cancer in vivo through one or both of the above mechanisms (mimicking MeHPLA and preventing its destruction). One study reported that subcutaneous administration of luteolin (at about 23 to 91 mg/kg) inhibited growth of transplanted human breast cancer cells in mice.25 The authors hypothesized that the results were related to type II binding or in-

creased MeHPLA availability. The equivalent human oral dose is about 1.5 to 5.8 grams per day.

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