RLIP inhibition suppresses breast-to-lung metastasis.

Breast tumor metastasis is a leading cause of cancer-related deaths worldwide. Breast cancer (BC) cells frequently metastasize to the lungs, where they pose a formidable therapeutic challenge. In the current study, we evaluated the anti-proliferative and anti-metastatic effects of 2'-hydroxyflavanone (2HF) and RLIP inhibition in an array of triple-negative BC cell lines and an orthotopic mouse model of breast-to-lung metastasis. Compared to control treatment, RLIP inhibition reduced in-vitro cell viability and suppressed the migratory and invasive potential of BC cells. In-vitro studies showed that 2HF treatment reduced the expression of RLIP, KRAS, pERK, pSTAT3, and pP70S6K. Further, mice orthotopically implanted with lung-seeking luciferase-expressing TMD231 cells were treated with 2HF (50 mg/kg, b.w.), RLIP antisense (RAS; 5 mg/kg, b.w.), RLIP antibody (Rab; 5 mg/kg, b.w.) or a combination of 2HF + RAS + Rab. 2HF-, RAS-, and Rab-treated mice exhibited significantly lower primary tumor weight and reduced lung metastasis compared to control mice. Mice treated with a combination of 2HF + RAS + Rab exhibited no metastasis and significantly lower tumor weight than the single agent-treated mice. Collectively, our results suggest that 2HF has potential to be combined with RLIP inhibition/depletion to more effectively suppress primary breast tumor growth and metastasis to the lungs.