Soy Promotes Juvenile Granulosa Cell Tumor Development in Mice and in the Human Granulosa Cell Tumor-Derived COV434 Cell Line1

Abstract

Soy attracts attention for its health benefits, such as lowering cholesterol or preventing breast and colon cancer. Soybeans contain isoflavones, which act as phytoestrogens. Even though isoflavones have beneficial health effects, a role for isoflavones in the initiation and progression of diseases including cancer is becoming increasingly recognized. While data from rodent studies suggest that neonatal exposure to genistein (the predominant isoflavone in soy) disrupts normal reproductive function, its role in ovarian cancers, particularly granulosa cell tumors (GCT), is largely unknown. Our study aimed to define the contribution of a soy diet in GCT development using a genetically modified mouse model for juvenile GCTs (JGCT; Smad1 Smad5 conditional double knockout mice) as well as a human JGCT cell line (COV434). While dietary soy cannot initiate JGCT development in mice, we show that it has dramatic effects on GCT growth and tumor progression compared to a soy-free diet. Loss of Smad1 and Smad5 alters estrogen receptor alpha (Esr1) expression in granulosa cells, perhaps sensitizing the cells to the effects of genistein. In addition, we found that genistein modulates estrogen receptor expression in the human JGCT cell line and positively promotes cell growth in part by suppressing caspase-dependent apoptosis. Combined, our work suggests that dietary soy consumption has deleterious effects on GCT development.

Smad4 Feedback Enhances BMPR1B Transcription in Ovine Granulosa Cells

“…Two core receptors, BMPR1B and BMPR2, were found to regulate granulosa cell apoptosis in ovaries of humans [45] and sheep [12], respectively. For R-Smads, SMAD1 regulated COV434 cell (a human granulosa cell tumor-derived cell line) apoptosis [46], and SMAD5 suppressed human granulosa cell apoptosis via the FasL-Fas pathway [47,48], but SMAD8 has not been reported to regulate GC apoptosis. Only one Co-SMAD, SMAD4 has been widely demonstrated to be a strong regulator of granulosa cell apoptosis in the ovary of various mammals, such as rodents [46] and pigs [15,17], but not sheep.…”

“…For R-Smads, SMAD1 regulated COV434 cell (a human granulosa cell tumor-derived cell line) apoptosis [46], and SMAD5 suppressed human granulosa cell apoptosis via the FasL-Fas pathway [47,48], but SMAD8 has not been reported to regulate GC apoptosis. Only one Co-SMAD, SMAD4 has been widely demonstrated to be a strong regulator of granulosa cell apoptosis in the ovary of various mammals, such as rodents [46] and pigs [15,17], but not sheep. Furthermore, in vivo , both SMAD4 and BMPR1B have been shown to be strongly involved in follicular atresia of domestic animals including sheep [14], pigs [4], and yaks [41].…”

Neonatal exposure of 17β-estradiol has no effects on mutagenicity of 7,12-dimethylbenz [a] anthracene in reproductive tissues of adult mice

“…Similar results also were observed in the incidence of mammary dysplasia in BALB/c mice [ 9 ]. Recently, soy diet has been found to promote granulose cell tumors in C57BL/6 J/129S7/Sv mixed mice [ 33 ]. Although there is genetic variation in physiological sensitivity to E2 between strains of mice, C57BL/6 is one of mouse strains that are highly responsive to E2 [ 34 , 35 ].…”

“…Although many aspects are still unknown, estrogen receptor-mediated effects on cell proliferation contribute to the weight of evidence for estrogen-mediated cancer [ 36 ]. It has been reported that genistein modulates estrogen-receptor expression and signaling in COV434 cells derived from a primary human juvenile granulose cell tumor, promoting cell growth [ 33 ]. In addition, the nature of genetic differences in mouse strains and subspecies is a major source of variation in susceptibility to endocrine disruption by estrogens [ 37 ].…”

Disruption of steroidogenesis: Cell models for mechanistic investigations and as screening tools

“…Pharmacological inhibition of the FSH receptor was found to inhibit COV434 cell proliferation [147]. Furthermore, incubation of COV434 cells with soy isoflavones, considered to act as phytoestrogens, promoted cell proliferation [148]. Incubation with 5 to 50 μM genistein led to increased expression of ERα and enhanced cell proliferation by repressing proapoptotic genes.…”