Xanthohumol suppresses oestrogen-signalling in breast cancer through the inhibition of BIG3-PHB2 interactions

• DOI: 10.1038/srep07355
• Publication Date: 2014-12-08T10:22:50Z
• Authors: Tetsuro Yoshimaru; Masato Komatsu; Etsu Tashiro; Masaya Imoto; Hiroyuki Osada; Yasuo Miyoshi; Junko Honda; Mitsunori Sasa; Toyomasa Katagiri
• Keywords: Flavonoids; Propiophenones; 0303 health sciences; Estrogen Receptor alpha; Apoptosis; Breast Neoplasms; Estrogens; Antineoplastic Agents, Phytogenic; Xenograft Model Antitumor Assays; Article; Tumor Burden; 3. Good health; Repressor Proteins; Disease Models, Animal; 03 medical and health sciences; Cell Line, Tumor; Prohibitins; Animals; Guanine Nucleotide Exchange Factors; Humans; Female; Cell Proliferation; Protein Binding; Signal Transduction

Xanthohumol (XN) is a natural anticancer compound that inhibits the proliferation of oestrogen receptor-α (ERα)-positive breast cancer cells. However, the precise mechanism of the antitumour effects of XN on oestrogen (E2)-dependent cell growth, and especially its direct target molecule(s), remain(s) largely unknown. Here, we focus on whether XN directly binds to the tumour suppressor protein prohibitin 2 (PHB2), forming a novel natural antitumour compound targeting the BIG3-PHB2 complex and acting as a pivotal modulator of E2/ERα signalling in breast cancer cells. XN treatment effectively prevented the BIG3-PHB2 interaction, thereby releasing PHB2 to directly bind to both nuclear- and cytoplasmic ERα. This event led to the complete suppression of the E2-signalling pathways and ERα-positive breast cancer cell growth both in vitro and in vivo, but did not suppress the growth of normal mammary epithelial cells. Our findings suggest that XN may be a promising natural compound to suppress the growth of luminal-type breast cancer.