Stimulation of breast cancer cellsin vitro by the environmental estrogen enterolactone and the phytoestrogen equol

Abstract

The phenolic lignans enterolactone and enterodiol appear periodically in women's urine, dependent upon synthesis from plant-derived lignans by the intestinal microflora. The phytoestrogen equol is also present in women's urine, and is also derived from a vegetarian diet. Antiestrogenic or antiproliferative actions of these compounds have been postulated and related to the observation that there is a reduced incidence of breast cancer associated with diet. We evaluated the estrogenic and antiestrogenic activity of these compounds using four sensitive assays in tissue culture, including the use of human breast cancer cell lines T47D and MCF-7. Unexpectedly, we found that enterolactone and enterodiol, as well as equol, are weak estrogens, and that enterolactone and equol could stimulate the growth of estrogen-dependent breast cancer cell lines. We suggest that these environmental agents can promote the growth of breast cancer, particularly hormone-dependent metastases that may be located near the gut or in the mesenteries or liver, where the concentration of these intestinally produced compounds would be highest. Treatment with an antiestrogen such as tamoxifen blocks the estrogenic activity of these compounds. In the absence of treatment with an antiestrogen such as tamoxifen, hormonal therapy to block steroidal estrogen synthesis in a patient with breast cancer could conceivably be circumvented by a vegeterian diet rich in the precursors to estrogenic compounds such as enterolactone and equol.

Flaxseed attenuates the tumor growth stimulating effect of soy protein in ovariectomized athymic mice with MCF‐7 human breast cancer xenografts

“…9,11,22 The mammalian lignan metabolites of plant lignans in FS, enterodiol and especially enterolactone, have also been shown to increase the MCF-7 cell proliferation. 39,40 However, these in vitro findings of mammalian lignans are not in agreement with the findings in vivo as no hormone responsive mammary tumor growth stimulating effect of FS 12,13,20 or enterolactone 11,15 has been demonstrated. This suggests that in the case of FS lignans or its mammalian metabolites, the in vitro proliferation assays alone may poorly predict the lignan responses in vivo possibly due to distinct mechanisms dominating in regulation of proliferation of MCF-7 cells in vitro and in vivo.…”

Mammalian lignans enterolactone and enterodiol, alone and in combination with the isoflavone genistein, do not promote the growth of MCF‐7 xenografts in ovariectomized athymic nude mice

“…Previous in vitro studies have shown that END has either no effect 20 or minimal growth modulating effects 21 on MCF-7 cells. Conversely, ENL has been reported to induce estrogenic effects by increasing MCF-7 cell proliferation 22 and the expression of the estrogen sensitive gene pS2.…”

“…Conversely, ENL has been reported to induce estrogenic effects by increasing MCF-7 cell proliferation 22 and the expression of the estrogen sensitive gene pS2. 20,21 However, in the presence of E2, ENL acts antiestrogenically by reducing MCF-7 cell proliferation. 22 ENL binds weakly to ERs 23 and transactivates ERs with a low potency, 13 suggesting that the mechanism of the ENL effect may be ER-mediated.…”

Dietary lariciresinol attenuates mammary tumor growth and reduces blood vessel density in human MCF‐7 breast cancer xenografts and carcinogen‐induced mammary tumors in rats

“…In several studies in vitro, enterolactone has been shown to stimulate the proliferation of estrogen-sensitive MCF-7 cells. [41][42][43][44][45][46] This stimulatory effect could be abolished with antiestrogens tamoxifen 41,45 and ICI-181,780. 46 In the presence of E2, enterolactone, enterodiol and the plant lignans secoisolariciresinol and lariciresinol have an additive effect on cell proliferation 47 suggesting that these compounds could act as ER agonists in breast cancer cells.…”