phytoestrogens and Osteolysis

The propensity of breast cancer to preferentially metastasize to the skeleton is well known. Once established in bone metastatic breast cancers have a poor prognosis due to their ability to promote extensive bone loss which augments tumor burden. Unfortunately, current anti-resorptive therapies for skeletal metastasis are typically prescribed after secondary tumors have formed and are palliative in nature. One group of compounds with the potential to reduce both tumor burden and osteolysis are phytoestrogens (PE), but the mechanisms mediating a beneficial effect are unclear. Therefore, the current study examined the effect of genistein and coumestrol alone or in combination on breast cancer cell number, expression of mediators of preferential skeletal metastasis, bone matrix attachment and tumor-induced osteoclast formation. Results showed that genistein and coumestrol significantly reduced viable cell number in an estrogen receptor dependent manner (p < 0.05), whereas combinations of PE had no effect. In addition, genistein and coumestrol significantly reduced expression of genes driving epithelial to mesenchymal transition (snail), bone attachment (CXCR4 and integrin αV) and osteolysis (PTHrP and TNF-α). In keeping with this genistein and coumestrol significantly suppressed attachment of breast cancer cells to bone matrix and inhibited tumor and RANKL-induced osteoclast formation. Our data suggests that phytoestrogens not only decrease breast cancer cell viability but also antagonize essential tumor bone interactions that establish and drive the progression of skeletal metastasis.

Topics: Bone Matrix; Bone Neoplasms; Breast Neoplasms; Cell Survival; Coumestrol; Epithelial-Mesenchymal Transition; Female; Genistein; Humans; MCF-7 Cells; Osteogenesis; Osteolysis; Phytoestrogens

We have reported that soy isoflavones are capable of preventing loss of bone mineral density (BMD) in rats due to ovariectomy. The intestinal microflora is important in rendering soy isoflavones bioavailability by facilitating their conversion to equol. Hence, substances that can modulate the intestinal microflora could affect the bioavailability of isoflavones. The purpose of this study was to examine whether combination of genistin and fructooligosaccharides (FOS), a prebiotic, can enhance the effects of soy isoflavones on bone in ovariectomized (OVX) female rats. Forty-eight 90-day-old female Sprague-Dawley rats were either sham-operated (Sham; one group) or Ovx (three groups) and were placed on dietary treatment for 50 days. The Sham and one Ovx group received a control diet, and the remaining Ovx groups received genistin-rich isoflavones diet (Ovx+G) or genistin-rich isoflavones and FOS diet (Ovx+G+FOS). After 50 days, blood and bone specimens were collected for analysis. The genistin-rich isoflavones diet was able to significantly increase the whole-body, right femur, and fourth lumbar BMD by 1.6%, 1.48%, and 1.3%, respectively in comparison with the Ovx control. The combination of genistin-rich isoflavones diet and 5% FOS further increased whole-body, right femur, and fourth lumbar BMD more compared to the genistin-rich isoflavones diet. Our findings suggest that although a genistin-rich isoflavones diet can increase the BMD in rats with Ovx-induced bone loss, combination of genistin-rich isoflavones and FOS had greater effect in preventing bone loss in this rat model.

Topics: Animals; Bone and Bones; Bone Density; Bone Density Conservation Agents; Drug Therapy, Combination; Estrogens; Female; Glycine max; Intestines; Isoflavones; Oligosaccharides; Osteolysis; Osteoporosis; Ovariectomy; Ovary; Phytoestrogens; Phytotherapy; Plant Extracts; Prebiotics; Rats