Glycone-rich Soy Isoflavone Extracts Promote Estrogen Receptor Positive Breast Cancer Cell Growth

ABSTRACT

Due to the association of hormone replacement therapy (HRT) with breast cancer risk, estrogenically active soy isoflavones are considered as an HRT alternative to alleviate menopausal symptoms. However, several recent reports challenged the health benefits of soy isoflavones and associated them with breast cancer promotion. While glyconic isoflavones are the major constituents of soybean seeds, due to their low cell permeability, they are considered to be biologically inactive. The glyconic isoflavones may exert their effects on membrane-bound estrogen receptors or could be converted to aglycones by extracellular β-glucosidases. Therefore, we hypothesized that despite their low cell permeability, soybean cultivars with high glyconic isoflavones may promote breast cancer cell growth. To test this, composition and estrogenic activity of isoflavones from 54 commercial soybean cultivars were determined. Soybean seeds produced in identical climate and growth conditions were used to minimize the effects of extraneous factors on isoflavone profile and concentrations. The glyconic daidzin concentration negatively correlated with genistin and with other aglycones. Relative to control, isoflavone extracts from 51 cultivars were estrogenic and promoted the growth of estrogen receptor positive (ER+) breast cancer cell line MCF-7 from 1.14 to 4.59 folds and other three cultivars slightly reduced the growth. Among these, extracts from three cultivars were highly estrogenic and promoted MCF-7 cell growth by 2.59–4.64 folds (P<0.005). Among six isoflavones, daidzin was positively associated with MCF-7 cell growth (P<0.005, r = 0.13966), whereas the negative correlation between genistin and MCF-7 cell growth was nearly significant (P≤0.0562, r = −0.026141). Furthermore, in drug interaction studies daidzin-rich isoflavone extracts antagonized tamoxifen, an ER inhibitor. Taken together, our results suggest that the glyconic daidzin-rich soy isoflavone extracts may exert estrogenic effects and promote ER+ breast cancer growth.

Conflict of interest

The authors declare non-financial competing interest.

Acknowledgments

KJ carried out estrogenic bioassays and TAM inhibitory assays, analyzed the data, and helped to draft the manuscript; SV optimized HPLC method and performed HPLC analysis of isoflavone extracts; SA performed extraction of isoflavones from soybean seeds; RC optimized bioassays with MCF-7 cells and assisted KJ in bioassays; VC conceived of the study, designed it, coordinated the study, analyzed the data, and drafted and edited the manuscript. All authors read and approved the final manuscript.

Funding

This study is supported by a TAMUC faculty research Enhancement award to VC, and NSF S-STEM scholarships to KJ and RC. We thank Ms. Lalitha Gaddipati, Alaa Qurban, and Ashjan Khalel for their help in organizing soybean seeds and isoflavone extraction.