Dave Bhuvanesh, Eason Renea R, Till S Renée, Geng Yan, Velarde Michael C, Badger Thomas M, Simmen Rosalia C M
Arkansas Children's Nutrition Center, Little Rock, AR 72202, USA.
Carcinogenesis. 2005 Oct;26(10):1793-803. doi: 10.1093/carcin/bgi131. Epub 2005 May 19.
The isoflavone genistein (GEN), a biologically active component of soy foods, is associated with reduced breast cancer risk in women who consume soy-rich diets. GEN has been reported to influence many biological processes, of which suppression of cell proliferation and stimulation of apoptosis are considered to be the major pathways underlying its inhibition of tumorigenesis. This study evaluated the mechanism by which diets containing GEN promote mammary epithelial cell death. We report that mammary glands of young adult female rats exposed from gestation day 4 to postnatal day 50, to AIN-93G diets containing as sole protein source, casein (CAS) supplemented with GEN, or soy protein isolate (SPI+) had increased apoptosis, relative to rats fed CAS diet devoid of GEN. Mammary gland proliferation was unaffected by diet. The increased apoptotic index in mammary glands of GEN and SPI+ rats was accompanied by increased levels of the tumor suppressor protein PTEN (phosphatase and tensin homolog deleted in chromosome ten), albeit enhanced mammary expression of the pro-apoptotic p21, Bax and Bok genes was observed only in GEN-fed rats. GEN-induced apoptosis in MCF-7 cells was concomitant with increased PTEN expression, and this was abrogated by PTEN siRNA. MCF-7 cells treated with serum from GEN- or SPI(+)-fed rats had increased apoptosis as well as increased levels of the PTEN transcript. PTEN siRNA attenuated the increased apoptotic response of MCF-7 cells to serum from rats fed SPI+ or GEN, although the inhibition to basal (CAS serum) apoptotic levels was achieved only for cells treated with GEN serum. Decreased p21 and Bok gene expression accompanied the inhibition of apoptosis by PTEN siRNA. Data implicate PTEN in the induction of apoptosis by GEN and suggest that the promotion of apoptosis leading to inhibition of tumorigenesis in vivo by diets containing GEN may also involve the distinct activities of yet unknown GEN metabolite(s) and/or other systemic factors induced by GEN.
异黄酮染料木黄酮（GEN）是大豆食品中的一种生物活性成分，与食用富含大豆饮食的女性患乳腺癌风险降低有关。据报道，GEN会影响许多生物学过程，其中抑制细胞增殖和刺激细胞凋亡被认为是其抑制肿瘤发生的主要途径。本研究评估了含GEN饮食促进乳腺上皮细胞死亡的机制。我们报告称，从妊娠第4天到出生后第50天，暴露于以酪蛋白（CAS）为唯一蛋白质来源并添加了GEN的AIN-93G饮食或大豆分离蛋白（SPI+）饮食的年轻成年雌性大鼠的乳腺，相对于喂食不含GEN的CAS饮食的大鼠，其细胞凋亡增加。饮食对乳腺增殖没有影响。GEN和SPI+大鼠乳腺中凋亡指数的增加伴随着肿瘤抑制蛋白PTEN（第10号染色体缺失的磷酸酶和张力蛋白同源物）水平的升高，尽管仅在喂食GEN的大鼠中观察到促凋亡p21、Bax和Bok基因的乳腺表达增强。GEN诱导MCF-7细胞凋亡与PTEN表达增加同时发生，而PTEN siRNA可消除这种现象。用来自喂食GEN或SPI(+)大鼠的血清处理的MCF-7细胞凋亡增加，同时PTEN转录本水平也增加。PTEN siRNA减弱了MCF-7细胞对来自喂食SPI+或GEN大鼠血清的凋亡反应增加，尽管仅对用GEN血清处理的细胞实现了对基础（CAS血清）凋亡水平的抑制。PTEN siRNA抑制凋亡伴随着p21和Bok基因表达的降低。数据表明PTEN参与了GEN诱导的凋亡，并表明含GEN饮食在体内通过促进凋亡导致肿瘤发生抑制可能还涉及GEN未知代谢产物和/或GEN诱导的其他全身因素的不同活性。
