Broussoflavonol B

A novel anticancer agent Broussoflavonol B downregulates estrogen receptor (ER)-alpha36 expression and inhibits growth of ER-negative breast cancer MDA-MB-231 cells.[Pubmed:23769740]

Eur J Pharmacol. 2013 Aug 15;714(1-3):56-64.

Estrogen receptor (ER)-negative breast cancers are aggressive and unresponsive to antiestrogens, and current therapeutic modalities for ER-negative breast cancer patients are usually associated with strong toxicity and side effects. Less toxic and more effective targeted therapies are urgently needed to treat this type of breast cancer. Here, we report that Broussoflavonol B, a chemical purified from the bark of the Paper Mulberry tree (Broussonetia papyrifera) exhibited potent growth inhibitory activity in ER-negative breast cancer MDA-MB-231 cells at sub-micromolar concentrations. Broussoflavonol B induced cell cycle arrest at both the G(0)/G(1) and G(2)/M phases accompanied by a downregulation of c-Myc protein, a upregulation of the cell cycle inhibitory proteins p16(INK4a), p19(INK4D) and p21(WAF1/CIP1) and a down-regulation of the expression levels of the G(2)/M regulatory proteins such as cyclin B1, cdc2 and cdc25C. Broussoflavonol B also induced apoptotic cell death characterized by accumulation of the annexin V- and propidium iodide-positive cells, and cleavage of caspases 8, 9 and 3. In addition, Broussoflavonol B treatment also decreased the steady state levels of the epidermal growth factor receptor (EGFR) and ER-alpha36, a variant of estrogen receptor-alpha, and restricted growth of the stem-like cells in ER-negative breast cancer MDA-MB-231 cells. Our results thus indicate that Broussoflavonol B is a potent growth inhibitor for ER-negative breast cancer cells and provide a rational for preclinical and clinical evaluation of Broussoflavonol B for ER-negative breast cancer therapy.

Downregulation of ER-alpha36 expression sensitizes HER2 overexpressing breast cancer cells to tamoxifen.[Pubmed:25973295]

Am J Cancer Res. 2015 Jan 15;5(2):530-44. eCollection 2015.

Tamoxifen provided a successful treatment for ER-positive breast cancer for many years. However, HER2 overexpressing breast cancer cells respond poorly to tamoxifen therapy presumably by pass. The molecular mechanisms underlying development of tamoxifen resistance have not been well established. Recently, we reported that breast cancer cells with high levels of ER-alpha36, a variant of ER-alpha, were resistant to tamoxifen and knockdown of ER-alpha36 expression in tamoxifen resistant cells with the shRNA method restored tamoxifen sensitivity, indicating that gained ER-alpha36 expression is one of the underlying mechanisms of tamoxifen resistance. Here, we found that tamoxifen induced expression of ER-alpha36-EGFR/HER2 positive regulatory loops and tamoxifen resistant MCF7 cells (MCF7/TAM) expressed enhanced levels of the loops. Disruption of the ER-alpha36-EGFR/HER2 positive regulatory loops with the dual tyrosine kinase inhibitor Lapatinib or ER-alpha36 down-regulator Broussoflavonol B in tamoxifen resistant MCF7 cells restored tamoxifen sensitivity. In addition, we also found both Lapatinib and Broussoflavonol B increased the growth inhibitory activity of tamoxifen in tumorsphere cells derived from MCF7/TAM cells. Our results thus demonstrated that elevated expression of the ER-alpha36-EGFR/HER2 loops is one of the mechanisms by which ER-positive breast cancer cells escape tamoxifen therapy. Our results thus provided a rational to develop novel therapeutic approaches for tamoxifen resistant patients by targeting the ER-alpha36-EGFR/HER2 loops.