Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages.

摘要: Obesity represents a risk factor for breast cancer development and therapy resistance, but the molecular players underling these links are unclear. Here, we identify role obesity-cytokine leptin in sustaining aromatase inhibitor (AI) resistant growth progression cancer. Using as experimental models MCF-7 cells surviving long-term treatment with AI anastrozole (AnaR) Ana-sensitive counterparts, found that AnaR expressed higher levels of its receptors (ObR) along constitutive activation downstream effectors. Accordingly, signaling inhibition reduced only cell motility, highlighting existence an autocrine loop mechanisms governing drug-resistant phenotypes. In agreement ObR overexpression, increasing doses were able to stimulate greater extent migration than sensitive cells. Moreover, contributed enhanced crosstalk between macrophages within tumor microenvironment. Indeed, AnaR, through secretion, modulated macrophage profiles increased motility CXCR4 signaling, evidenced by RNA-sequencing, real-time PCR, immunoblotting. Reciprocally, activated coculture systems. conclusion, acquired resistance is accompanied leptin-driven phenotype, potential clinical benefit targeting this cytokine network hormone-resistant cancers, especially obese women.