Leptin-elicited PBX3 confers letrozole resistance in breast cancer

in Endocrine-Related Cancer
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  • 1 Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China

Correspondence should be addressed to X Liu or Q Zhang: KjkLXY@126.com or zhangqiang8220@163.com
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Aberrant leptin signaling and overexpression of fibroblast growth factor receptor 1 (FGFR1) are both implicated in the pathogenesis of letrozole resistance in breast cancer (BCa), but it remains unknown whether these two pathways are involved in letrozole resistance in a coordinated manner. Here, we demonstrate that expression levels of the pre-B-cell leukemia homeobox transcription factor 3 (PBX3), a pioneer factor that governs divergent biological processes, were significantly upregulated in letrozole-resistant BCa cells and tissues, and this upregulation correlated to a poorer progression-free survival in patients. By leveraging a patient-derived xenograft model with pharmacological approaches, we demonstrated that leptin activated PBX3 expression in a STAT3 (signal transducer and activator of transcription 3)-dependent manner. Our loss- and gain-of-function study further showed that PBX3 attenuated response to letrozole by potentiating BCa cell survival and anchorage-independent growth in BCa cells. By profiling BCa cells with ectopic PBX3 expression, we revealed that PBX3 conferred letrozole resistance via transactivation of the FGFR1 signaling, and this molecular event must coordinate a synergistic transcription activation programs through interacting with MTA1-HDAC2 (metastasis-associated 1-histone deacetylase 2) complex. Overall, the available data reveal a novel role of leptin/PBX3 cascade linking energy homeostasis (i.e. hyperleptinemia) and endocrine therapy failure (i.e. letrozole resistance) in BCa.

Supplementary Materials

    • Supplemental Table 1 The clinicopathological characteristics of the 105 BCa patients who received letrozole-based endocrine therapy.
    • Supplementary Table 2 Sources of antibodies and the working dilutions that were used in the current study
    • SFig. 1 Genetic backgrounds of BCa cells used in the study.
    • SFig. 2 Circulating leptin levels in our 105-patient cohort.
    • SFig. 3 Effects of ectopic overexpression of PBX3 on chemosensitivity to exemestane and anastrozole in MCF7 and MDA-MB-415 cells. (a) BCa cells with different transfections were seeded onto a 96-well plate at the density of 1&#x00D7;104 cells/well. The next day, cells were washed and treated with 10-5 M of exemestane for different durations. Cell growth was then assessed using MTT assay (*P<0.05 and **P<0.01). (b) BCa cells with different transfections were seeded onto a 96-well plate at the density of 1&#x00D7;104 cells/well. The next day, cells were washed and treated with 10-5 M of anastrozole for different durations. Cell growth was then assessed using MTT assay.

 

Society for Endocrinology

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