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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #172857
Title: THE TUMOR SUPPRESSOR PTEN MEDIATES THE PRO-APOPTOTIC ACTIVITY OF DIETARY GENISTEIN ON MAMMARY EPITHELIAL CELLS: IMPLICATIONS FOR MAMMARY CANCER PROTECTION

Author
item DAVE, BHUVANESH - UAMS/ACNC
item EASON, RENEA - ACNC
item TILL, RENEE - ACNC
item GENG, YAN - UAMS/ACNC
item VELARDE, MICHAEL - UAMS/ACNC
item BADGER, THOMAS - UAMS/ACNC
item SIMMEN, ROSALIA - UAMS/ACNC

Submitted to: American Association of Cancer Research
Publication Type: Abstract Only
Publication Acceptance Date: 2/1/2005
Publication Date: 3/30/2005
Citation: Dave, B., Eason, R.R., Till, R.S., Geng, Y., Velarde, M.C., Badger, T.M., Simmen, R.C. 2005. The tumor suppressor PTEN mediates the pro-apoptotic activity of dietary genistein on mammary epithelial cells: implications for mammary cancer protection. Proceedings American Association of Cancer Research. 46:2663.

Interpretive Summary: Asian populations who consume diets rich in soy foods have lower incidence of certain cancers, including breast cancer. We have previously demonstrated that rats fed soy-containing diets have lower levels of experimentally-induced cancers. One of the major components in soy foods that may be responsible for the protective effects of soy foods is genistein. Our studies examined how dietary soy and genistein might protect against mammary tumor formation in a rat model of carcinogenesis. We found that ingestion of soy protein isolate and its major isoflavone component genistein increased the death of cells in mammary tissues. This cell death process is thought to be how the body eliminated damaged cells that go on to produce cancers. This increase in cell death is associated with “turning on” specific genes, most important of which may be a gene that is responsible for suppressing tumor development, call PTEN. Hence, we postulate that diets containing genistein can be protective against mammary tumors by eliminating mammary cells likely give rise to tumors and the tumor suppressor gene PTEN may be involved.

Technical Abstract: Dysregulation of the apoptotic pathway is a hallmark of tumor cells and underlies tumor progression, metastasis, and aggressiveness. We previously reported that AIN-93G diet made with soy protein isolate (SPI+) as the sole protein source protected against DMBA- and NMU-induced tumorigenesis in Sprague-Dawley rats, relative to the control casein (CAS) diet. Soy isoflavones have also been shown to protect against carcinogen-induced mammary tumors in rodents. The present study evaluated if dietary soy and its major isoflavone genistein alter the frequency of apoptosis in mammary glands, leading to protection against tumor formation. Mammary tissues of postnatal day 50 rats lifetime exposed to diets of CAS, SPI+ (containing 377 mg total genistein/kg diet), and CAS + genistein (GEN; added at 250 mg/kg diet) were analyzed for proliferative status (PCNA), apoptosis (TUNEL) and expression levels of the pro-apoptotic/tumor suppressor PTEN mRNA (real-time PCR) and protein (immunohistochemistry). Rats fed SPI+ or GEN diets had increased apoptosis in terminal end bud (TEB), lobular (LOB), and ductal epithelial (DE) structures (P<0.05) than in those fed CAS. Proliferation in these mammary structures did not differ among diets. PTEN transcript levels in whole mammary tissues were higher in rats fed GEN (P<0.005) than in those fed CAS or SPI+. However, the levels of immunoreactive PTEN protein in LOB and DE, but not in TEB, were higher in SPI+ and GEN (P<0.05) than in CAS-fed rats. Relative to the CAS group, mammary tissues from the GEN group had higher p21 and Bax (P <0.05) and lower p53 (P=0.04) transcript levels. Sera from rats fed SPI+ or GEN (added at 1% final concentration) stimulated apoptosis of the breast cancer cell line MCF-7 (P=0.1 and P=0.002, respectively) and of primary cultures of mammary epithelial cells isolated from CAS-fed rats (P<0.05). The addition of small interfering RNA (siRNA; 50 nM) directed against PTEN reduced the numbers of apoptotic cells in MCF-7 cells treated with GEN sera (P<0.03), but not in those treated with CAS sera. Results indicate that dietary exposure to SPI+ or GEN promotes apoptosis in mammary structures concomitant with increased PTEN expression. Further, the pro-apoptotic activity of GEN is directly, if not entirely, mediated by the PTEN signaling pathway. Given that undifferentiated cells with high tumorigenic potential likely arise during the early growth stages of the mammary gland, removal of these cells by apoptosis may provide an advantage against subsequent and cumulative carcinogenic insults.