Recurrence of metastatic breast cancer stemming from acquired endocrine and chemotherapy resistance remains a health burden for women with luminal (ER+) breast cancer. Disseminated ER+ tumor cells can remain viable but quiescent for years to decades. Contributing factors to metastatic spread include the maintenance and expansion of breast cancer stem cells (CSCs). Breast CSCs frequently exist as a minority population in therapy resistant tumors. In this study, we show that cytoplasmic complexes composed of steroid receptor (SR) co-activators, PELP1 and SRC-3, modulate breast CSC expansion through upregulation of the HIF-activated metabolic target genes PFKFB3 and PFKFB4. Seahorse metabolic assays demonstrated that cytoplasmic PELP1 influences cellular metabolism by increasing both glycolysis and mitochondrial respiration. PELP1 interacts with PFKFB3 and PFKFB4 proteins, and inhibition of PFKFB3 and PFKFB4 kinase activity blocks PELP1-induced tumorspheres and protein–protein interactions with SRC-3. PFKFB4 knockdown inhibited in vivo emergence of circulating tumor cell (CTC) populations in mammary intraductal (MIND) models. Application of PFKFB inhibitors in combination with ER targeted therapies blocked tumorsphere formation in multiple models of advanced breast cancer including tamoxifen (TamR) and paclitaxel (TaxR) resistant models, murine tumor cells, and ER+ patient-derived organoids (PDxO). Together, our data suggest that PELP1, SRC-3, and PFKFBs cooperate to drive ER+ tumor cell populations that include CSCs and CTCs. Identifying non-ER pharmacological targets offers a useful approach to blocking metastatic escape from standard of care ER/estrogen (E2)-targeted strategies to overcome endocrine and chemotherapy resistance.
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Acknowledgements This work was supported by NIH grants R01 CA236948 (JHO, CAL), R01 CA229697 (CAL), F32 CA210340 (THT), T32 HL007741 (THT), U54 CA224076 (BEW), R01 CA248158-01 (CODS), and R01 AG069727-01 (CODS). ACS Institutional Research Grant #124166-IRG-58-001-52-IRG5 (JHO), University of Minnesota Masonic Cancer Center (CAL, JHO), the Tickle Family Land Grant Endowed Chair in Breast Cancer Research (CAL), National Center for Advancing Translational Sciences of the NIH Award UL1TR000114 (JHO), and Department of Defense W81XWH-14-1-0417 (BEW). We thank Bruce Lindgren for biostatistics support, and the Masonic Cancer Center Biostatistics and Bioinformatics, Analytical Biochemistry, University Imaging Core (UIC), and Flow Cytometry cores. We also thank Zohar Sachs and Michael Franklin for critical reading of this manuscript.
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.