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PELP1/SRC-3-dependent regulation of metabolic PFKFB kinases drives therapy resistant ER+ breast cancer

Oncogene volume 40, pages 4384–4397 (2021)Cite this article

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Abstract

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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Fig. 1: PELP1-induced gene expression is altered in 3D conditions.
Fig. 2: PELP1 cytoplasmic signaling upregulates HIF-activated metabolic pathways.
Fig. 3: PFKFB inhibition blocks PELP1/SRC-3 signaling.
Fig. 4: PFKFB4 knockdown abrogates cyto PELP1 CTCs in MIND xenografts.
Fig. 5: Therapy resistant models phenocopy cyto PELP1 cancer biology.
Fig. 6: Endocrine therapies exhibit combinatorial effects with PELP1 complex inhibitors.
Fig. 7: Co-treatments in preclinical ER+ PDxO models target CSCs.

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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.

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  1. These authors contributed equally: Carol A. Lange, Julie H. Ostrander

Authors and Affiliations

  1. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

    Thu H. Truong, Elizabeth A. Benner, Kyla M. Hagen, Nuri A. Temiz, Carlos Perez Kerkvliet, Ying Wang, Carol A. Lange & Julie H. Ostrander

  2. Institute for Health Informatics, University of Minnesota, Minneapolis, MN, USA

    Nuri A. Temiz

  3. Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA

    Emilio Cortes-Sanchez, Chieh-Hsiang Yang, Katrin P. Guillen & Bryan E. Welm

  4. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    Emilio Cortes-Sanchez, Chieh-Hsiang Yang, Katrin P. Guillen & Bryan E. Welm

  5. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

    Marygrace C. Trousdell & Camila O. Dos Santos

  6. University of Minnesota Informatics Institute, University of Minnesota, Minneapolis, MN, USA

    Thomas Pengo

  7. Department of Surgery, University of Utah, Salt Lake City, UT, USA

    Bryan E. Welm

  8. James Graham Brown Cancer Center, Department of Medicine (Division of Medical Oncology and Hematology), University of Louisville, Louisville, KY, USA

    Sucheta Telang

  9. Department of Medicine (Division of Hematology, Oncology, and Transplantation), University of Minnesota, Minneapolis, MN, USA

    Carol A. Lange & Julie H. Ostrander

  10. Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA

    Carol A. Lange

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Correspondence to Carol A. Lange or Julie H. Ostrander.

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CAL is a Scientific Advisory Board Member for Context Therapeutics, Inc. BEW, EC-S, KPG, and C-HY may receive financial compensation from intellectual property and tangible property licenses managed by the University of Utah. The remaining authors have nothing to disclose.

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Truong, T.H., Benner, E.A., Hagen, K.M. et al. PELP1/SRC-3-dependent regulation of metabolic PFKFB kinases drives therapy resistant ER+ breast cancer. Oncogene 40, 4384–4397 (2021). https://doi.org/10.1038/s41388-021-01871-w

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