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

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.

• Authors: Thu H Truong, Elizabeth A Benner, Kyla M Hagen, Nuri A Temiz, Carlos Perez Kerkvliet, Ying Wang, Emilio Cortes-Sanchez, Chieh-Hsiang Yang, Marygrace C Trousdell, Thomas Pengo, Katrin P Guillen, Bryan E Welm, Camila O Dos Santos, Sucheta Telang, Carol A Lange, Julie H Ostrander
• Journal: Oncogene (Oncogene) Vol. 40 Issue 25 Pg. 4384-4397 (06 2021) ISSN: 1476-5594 [Electronic] England
• PMID: 34103681 (Publication Type: 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.)

Chemical References

• Co-Repressor Proteins
• Estrogens
• PELP1 protein, human
• Receptors, Estrogen
• Transcription Factors
• Tamoxifen
• NCOA3 protein, human
• Nuclear Receptor Coactivator 3
• Phosphofructokinase-2
• Paclitaxel

Topics

• Animals
• Breast (pathology)
• Breast Neoplasms (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Co-Repressor Proteins (genetics)
• Drug Resistance, Neoplasm (genetics)
• Estrogens (genetics)
• Female
• Gene Expression Regulation, Neoplastic (genetics)
• Humans
• MCF-7 Cells
• Mice
• Neoplastic Stem Cells (drug effects, pathology)
• Nuclear Receptor Coactivator 3 (genetics)
• Paclitaxel (pharmacology)
• Phosphofructokinase-2 (genetics)
• Phosphorylation (genetics)
• Receptors, Estrogen (genetics)
• Tamoxifen (pharmacology)
• Transcription Factors (genetics)
• Up-Regulation (genetics)