PELP1/SRC-3-dependent regulation of metabolic 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. PFKFB inhibitors exhibited combinatorial effects in conjunction with ER targeted therapies in breast cancer cells, including tamoxifen resistant (TamR) and paclitaxel resistant (TaxR) models and ER+ patient-derived organoids (PDxO). Finally, PFKFB4 knockdown resulted in decreased circulating tumor cell (CTC) populations in mammary intraductal (MIND) models. 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.

Relationship between metabolic reprogramming and drug resistance in breast cancer

“…Combining an inhibitor of PFKFB3 with TAM suppresses the growth of both TAMR LCC9 and MCF-7 cells, demonstrating the role of PFKB3 in TAM resistance (45). A combination of PFKFB inhibitors and ER-targeted therapies block tumorsphere formation in several models of advanced breast cancer, such as tamoxifen (TamR)-and paclitaxel (TaxR)resistant cell models, ER+ patient-derived organoids (PDxO) and murine tumor cells (46).…”