SAT-300 Liquiritigenin Enhances Growth Inhibition Of TNBC By The Cholesterol Biosynthesis Inhibitor RO 48-8071

Abstract Disclosure: Y. Liang: None. S.M. Hyder: None. Approximately 15-20% of human breast cancers are classified as triple-negative (TNBC), because they are devoid of estrogen and progesterone receptors (ER, PR), and Her-2-neu (epidermal growth factor receptors), the three identifiable molecular targets for chemotherapy. Patients diagnosed with TNBCs are treated with conventional toxic chemotherapy regimens, which are non-specific and almost always lead to resistance. These patients have poor prognosis due to the emergence of drug-resistant cells that lead to tumor metastasis. Estrogens (E) are essential steroid hormones that regulate several physiological functions in humans. The diverse biological effects of E are mediated by the specific ER, ERα and ERβ. While TNBC are devoid of ERα, ERβ, which is anti-proliferative and is classified as a tumor suppressor, is present in TNBC cells. Cholesterol is a vital component of cell growth. With this in mind, we used RO 48-8071 ([4’-[6-(Allylmethylamino)hexyloxy]-4-bromo-2’-fluorobenzophenone fumarate (RO) to inhibit oxidosqualene cyclase, an enzyme downstream of HMGCoA reductase that is involved in cholesterol biosynthesis. Previously we showed that RO (1-50 μM) blocked the proliferation of TNBC cells, and surprisingly also induced ERβ. In the present investigation we determined whether upregulation of ERβ in TNBC by RO can be exploited to further suppress growth of TNBC cells. Liquiritigenin (LQ), a non-toxic, plant-derived ERβ agonist, was used in combination with RO. We found that RO (1-50 μM) inhibited proliferation of TNBC cells and reduced cell viability as determined by SRB assay, and that a combination of RO and LQ (10 μM and 100-200 μM respectively) further reduced cell viability in vitro, suggesting that modulating ERβ activity in TNBC cells could be a productive means by which to control TNBC. Xenograft studies were performed with MDA-MB-231 cells in nude mice, to determine whether LQ and RO exert similar effects in vivo. A combination of LQ + RO increased the suppressive effects compared with RO alone. IHC of RO- and LQ-treated tumor sections from MDA-MB-231 xenografts showed increased levels of ERβ but not ERα protein, increased apoptosis (TUNEL) and reduced angiogenesis (VEGF and CD-31 expression). We conclude that LQ increases the suppressive effect of RO in TNBC in part due to an off-target effect of RO that increases ERβ levels in TNBC cells. Combinations of RO and ERβ agonists should be considered for TNBC therapy. Presentation: Saturday, July 12, 2025