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 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. Significance: 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.

中文翻译：

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PELP1 / SRC-3依赖的代谢激酶调节可驱动治疗抵抗性ER +乳腺癌

源于内分泌和化疗耐药的转移性乳腺癌的复发仍然是管腔（ER +）乳腺癌女性的健康负担。弥散的ER +肿瘤细胞可以保持活力，但可以静止数年至数十年。转移扩散的因素包括乳腺癌干细胞（CSCs）的维持和扩增。乳腺癌CSC经常以少数人群存在于抗药性肿瘤中。在这项研究中，我们表明，由类固醇受体（SR）共激活剂PELP1和SRC-3组成的细胞质复合物通过上调HIF激活的代谢靶基因PFKFB3和PFKFB4来调节乳腺CSC的扩增。海马代谢测定表明，胞质PELP1通过增加糖酵解和线粒体呼吸作用影响细胞代谢。PELP1与PFKFB3和PFKFB4蛋白质相互作用，并且抑制PFKFB3和PFKFB4激酶活性会阻止PELP1诱导的肿瘤球以及与SRC-3的蛋白质相互作用。PFKFB4组合体抑制乳腺导管内（MIND）模型中循环肿瘤细胞（CTC）人口的体内出现。PFKFB抑制剂与ER靶向疗法的结合可在多种晚期乳腺癌模型中阻止肿瘤球的形成，包括他莫昔芬（TamR）和紫杉醇（TaxR）耐药模型以及ER +患者衍生的类器官（PDxO）。总之，我们的数据表明，PELP1，SRC-3和PFKFB共同驱动包括CSC和CTC在内的ER +肿瘤细胞群体。意义：