Prepubertal genistein exposure affects erbB2/Akt signal and reduces rat mammary tumorigenesis

Abstract

Breast cancer is the most common malignancy in women worldwide and pharmaceutical agents have therapeutic and preventive effects in breast cancer. The human epidermal growth factor receptor 2/neu is one of the most important oncogenes in human breast cancer. Prepubertal exposure to endogenous estradiol and a phytoestrogen, genistein (Gen), has been shown to reduce future breast cancer risk. Gen downregulates tyrosine kinase regulated protein expression and reduces prostate cancer. In this study, the effects of prepubertal exposure to Gen on rat mammary carcinogenesis and the erbB2/Akt signal pathway were investigated. Prepubertal female Sprague-Dawley rats were daily exposed to Gen at 125 mg/kg (Gen-1) and 500 mg/kg (Gen-5) from postnatal days 22-28. Subsequently, the rats were given a single dose of 100 mg/kg 7.12-dimethylbenz [a] anthracene on postnatal day 42 to induce mammary tumor. The mRNA expression of erbB2 and amplified in breast cancer 1 (AIB1) was detected by reverse transcription-polymerase chain reaction. The protein levels of proliferating cell nuclear antigen (PCNA), erbB2, phosphotyrosine protein, Akt, and p-Akt were detected by immunohistochemistry and Western blotting. The activity of protein tyrosine kinase (PTK) was detected by liquid scintillation counting. The percentage of rats with mammary tumors in breast cancer model (BCM), Gen-1, and Gen-5 was 71.43, 52.38, and 33.34%, respectively. The incidence of 7.12-dimethylbenz [a] anthracene-induced mammary tumors significantly decreased in Gen-5 compared with that in BCM. The mRNA levels of AIB1 and erbB2 and the protein levels of erbB2, p-Akt, and PCNA protein expression were downregulated for a long time in the mammary tumors in Gen-5 groups. The activity of PTK was also decreased for a long time. However, the total Akt protein expression did not change significantly among BCM, Gen-1, and Gen-5. Prepubertal exposure of Sprague-Dawley female rats to 500 mg/kg Gen can reduce later breast cancer risk and its protective effect is associated with persistent downregulation of the expression of erbB2, p-Akt, AIB1, and PCNA and with low PTK activity in the mammary tumor. Our results suggest that erbB2/Akt signaling plays a role in tumor formation and targeting erbB2/Akt signaling with prepubertal exposure to Gen may provide greater efficacy to the current therapies used to treat tumors.

Endocrine-active chemicals in mammary cancer causation and prevention

“…This has subsequently been confirmed by other groups [77,78]. Using a similar prepubertal genistein dietary exposure model (100 or 500 mg genistein/kg diet on postnatal days [22][23][24][25][26][27][28] coupled to DMBA at PND 50, Peng et al found that genistein exposure significantly down-regulated the expression of PCNA, erbB2, Akt, and phospho-Akt in the mammary gland [79].…”

Genistein, an epigenome modifier during cancer prevention

“…[10][11][12] A recent in vivo study indicated that pre-pubertal genistein exposure suppressed chemical-induced mammary tumors. 13 Dietary genistein has also been reported to reduce chemical-induced prostate cancer 14 and colon cancer 15,16 in rats. In vitro studies conducted in different cancer cell lines confirmed that by affecting various cellular targets, including several critical tumor suppressor genes, genistein treatment repressed cancer cell proliferation, [17][18][19] induced apoptosis [19][20][21] and led to cell cycle arrest.…”

Clobetasol synergistically diminishes Ciz1 expression with genistein in U937 cells

“…Genistein is one of the known isoflavones, which is a group of compounds found in soybeans. Genistein inhibits the oncogenic signal mediated by tyrosine kinases, such as EGF receptor, ErbB2 and Src family kinases (8). We speculated that other tyrosine kinase inhibitors could also reduce Ciz1 expression.…”