The soy isoflavone genistein promotes apoptosis in mammary epithelial cells by inducing the tumor suppressor PTEN

• Published in: Carcinogenesis (New York) Vol. 26; no. 10; pp. 1793 - 1803
• Main Authors: Dave, Bhuvanesh, Eason, Renea R., Till, S.Renée, Geng, Yan, Velarde, Michael C., Badger, Thomas M., Simmen, Rosalia C.M.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.10.2005; Oxford Publishing Limited (England)
• Subjects: 12 dimethylbenz[a]anthracene; AIN; American Institute of Nutrition; Animals; Anticarcinogenic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Breast Neoplasms; Carcinogenesis, carcinogens and anticarcinogens; CAS; casein; Cell Division - drug effects; Cell Line, Tumor; DMBA; DNA Primers; Epithelial Cells - cytology; Epithelial Cells - drug effects; Female; GEN; genistein; Genistein - pharmacology; gestation day; Humans; Mammary Glands, Animal - cytology; Mammary Glands, Animal - drug effects; Medical sciences; PCNA; phosphatase and tensin homolog deleted in chromosome ten; phosphatidylinositol-3-kinase; Phosphoric Monoester Hydrolases - genetics; PI3-K; PND; Polymerase Chain Reaction; postnatal day; Pregnancy; Prenatal Exposure Delayed Effects; proliferating cell nuclear antigen; PTEN; PTEN Phosphohydrolase; qPCR; quantitative real-time polymerase chain reaction; Rats; Rats, Sprague-Dawley; SEM; siRNA; small interfering RNA; soy protein isolate; SPI; standard error of the mean; terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick-end labeling; Tumor Suppressor Proteins - genetics; Tumors; TUNEL; Phytoestrogen; Cell death; Genistein; Epithelial cell; PTEN Gene; Mammary gland; Soybean; In vitro; Isoflavone derivatives; Apoptosis; Tumor suppressor gene
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgi131

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.