Abstract
PurposeClinical trials and epidemiological evidence have shown that combined estrogen/progestin hormone replacement therapy, but not estrogen therapy alone, increases breast cancer risk in post-menopausal women. Previously we have shown that natural and synthetic progestins, including the widely used synthetic progestin medroxyprogesterone acetate (MPA), increase production of a potent angiogenic factor, vascular endothelial growth factor (VEGF), in human breast cancer cells, potentially providing an explanation for progestin’s mechanism of action. Here, we tested the effects of luteolin (LU), a flavonoid commonly found in fruits and vegetables, on inhibiting progestin-dependent VEGF induction and angiogenesis in human breast cancer cells, inhibiting stem cell-like characteristics, as well as breast cancer cell xenograft tumor growth in vivo and expression of angiogenesis markers.MethodsViability of both T47-D and BT-474 cells was measured using sulforhodamine B assays. Enzyme-linked immunosorbent assays were used to monitor VEGF secretion from breast cancer cells. Progestin-dependent xenograft tumor growth was used to determine LU effects in vivo. CD31 immunohistochemistry was used to determine blood-vessel density in xenograft tumors. CD44 expression, aldehyde dehydrogenase activity, and mammosphere-formation assays were used to monitor stem cell-like characteristics of breast cancer cells.ResultsLuteolin treatment reduced breast cancer cell viability, progestin-dependent VEGF secretion from breast cancer cells, and growth of MPA-dependent human breast cancer cell xenograft tumors in nude mice. LU treatment also decreased xenograft tumor VEGF expression and blood-vessel density. Furthermore, LU blocked MPA-induced acquisition of stem cell-like properties by breast cancer cells.ConclusionsLuteolin effectively blocks progestin-dependent human breast cancer tumor growth and the stem cell-like phenotype in human breast cancer cells.
Highlights
Breast cancer is the most commonly diagnosed form of cancer and the second-leading cause of cancer-related death in American women
A progestin component is administered to women with an intact uterus to prevent endometrial cancer; its inclusion in the hormone replacement therapy (HRT) formulation has been found to increase the incidence of breast cancer significantly compared with that in post-menopausal women undergoing HRT containing estrogen alone (Ross et al 2000; Chlebowski et al 2003; Writing Group for the Women’s Health Initiative Investigators 2002)
To examine LU’s ability to block progestin-induced secretion of vascular endothelial growth factor (VEGF) from breast cancer cells, T47-D cells were treated for 18 h with medroxyprogesterone acetate (MPA), both with and without LU or RU-486, release of VEGF into the culture medium measured
Summary
Breast cancer is the most commonly diagnosed form of cancer and the second-leading cause of cancer-related death in American women. A subset of both newly diagnosed cases and breast cancer-related deaths is linked to the use of hormone replacement therapy (HRT) containing a combination of estrogen and progestin in post-menopausal women (Ross et al 2000; Chlebowski et al 2003). A progestin component is administered to women with an intact uterus to prevent endometrial cancer; its inclusion in the HRT formulation has been found to increase the incidence of breast cancer significantly compared with that in post-menopausal women undergoing HRT containing estrogen alone (Ross et al 2000; Chlebowski et al 2003; Writing Group for the Women’s Health Initiative Investigators 2002). The use of HRT has become increasingly controversial, in the United States an estimated 1.6 million women take combined estrogen/ progestin HRT to alleviate the symptoms of menopause (Tsai et al 2011)
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