Abstract 4159: Therapeutic effects of luteolin against progestin-dependent breast cancer involves induction of apoptosis, and suppression of both stem-cell-like cells and angiogenesis
Authors: Cook Matthew Thomas , Liang Yayun , Goyette Sandy , Mafuvadze Benford , Besch-Williford Cynthia , Hyder Salman 
Published: August 2015

Clinical and epidemiological evidence show that combined estrogen (E) and progestin (P) hormone replacement therapy (HRT) increases the risk of breast cancer in postmenopausal women. Tumor progression is dependent on cell survival and angiogenesis, which provides nutrients vital to the developing cancer. We have shown that physiological levels of P (10 nM), including medroxyprogesterone acetate (MPA), which is widely used in HRT, increases the production of the potently angiogenic vascular endothelial growth factor (VEGF), in human breast cancer cells both in vitro and in vivo. The anti-progestin RU-486 blocks this effect, suggesting the involvement of progesterone receptors in the process (Int J Cancer, 2001, 92:469). Evidence from our laboratory using in vivo breast cancer models suggests that P accelerates the development of tumors from latent tumorigenic cells, leading to the development of palpable tumors (Cancer Res., 2007, 67:9929; Clin Can Res, 2006, 12:4062), a process that may be attributed to increased production of VEGF. RU-486 blocks P-dependent VEGF production and thereby reduces tumor growth; however, the anti-progestin has severe side-effects and therefore cannot be used in the long-term. Recently, we have been studying less toxic naturally-occurring compounds for their ability to block P-dependent tumor progression. We tested the effects of the flavonoid luteolin, which is commonly found in fruits and vegetables, on proliferation of BT-474 and T47-D breast cancer cells and their production of VEGF. Luteolin treatment (10-100 μM) for 24 h reduced tumor cell viability, induced apoptosis, blocked P-dependent increases in CD44 high stem-cell-like cells, and blocked production of P-dependent VEGF induction in vitro. Interestingly, luteolin also reduced the ability of cells to form mammospheres, a characteristic of self-renewable cells. Furthermore, luteolin (20 mg/kg, i.p.) suppressed the growth of MPA-dependent BT-474 human xenograft tumors in nude mice. Immunohistochemical analysis showed that luteolin significantly reduced P-induced VEGF production in vitro (p&lt;0.05). Our findings strongly suggest that luteolin disrupts tumor progression by blocking several processes that are vital to P-dependent tumor development. We contend therefore that luteolin is a compound with valuable therapeutic properties against P-dependent human breast cancer.

Supported by a COR award from the College of Veterinary Medicine.

Citation Format: Matthew Thomas Cook, Yayun Liang, Sandy Goyette, Benford Mafuvadze, Cynthia Besch-Williford, Salman Hyder. Therapeutic effects of luteolin against progestin-dependent breast cancer involves induction of apoptosis, and suppression of both stem-cell-like cells and angiogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4159. doi:10.1158/1538-7445.AM2015-4159