scholarly journals Steroid Receptor Co-Activators Regulate Metabolic Kinases to Drive Therapy Resistant ER+ Breast Cancer

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1031-A1032
Author(s):  
Thu Ha Truong ◽  
Elizabeth A Benner ◽  
Kyla M Hagen ◽  
Nuri A Temiz ◽  
Carlos Perez Kerkvliet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Target Genes ◽  
Chemotherapy Resistance ◽  
Metastatic Breast ◽  
Steroid Receptor ◽  
Therapy Resistance ◽  
Minority Population ◽  
Contributing Factors

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 are poorly proliferative and frequently exist as a minority population in therapy resistant tumors. Our objective is to define novel signaling pathways that govern therapy resistance in ER+ breast cancer. 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 ER+ mammary intraductal (MIND) xenografts. 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 cells 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 in ER+ breast cancer.

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

2020 ◽  
Author(s):  
Thu H. Truong ◽  
Elizabeth A. Benner ◽  
Kyla M. Hagen ◽  
Nuri A. Temiz ◽  
Carlos Perez Kerkvliet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cell ◽  
Protein Interactions ◽  
Target Genes ◽  
Chemotherapy Resistance ◽  
Metastatic Breast ◽  
Circulating Tumor Cell ◽  
Minority Population ◽  
Contributing Factors

ABSTRACTRecurrence 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.SignificanceIdentifying 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.

scholarly journals Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer

2017 ◽  
Vol 114 (43) ◽  
pp. E9066-E9075 ◽  
Author(s):  
Pasquale Sansone ◽  
Claudia Savini ◽  
Ivana Kurelac ◽  
Qing Chang ◽  
Laura Benedetta Amato ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormonal Therapy ◽  
Horizontal Transfer ◽  
Metastatic Breast ◽  
Therapy Resistance ◽  
Peripheral Circulation ◽  
Functional Studies ◽  
Xenograft Models

The horizontal transfer of mtDNA and its role in mediating resistance to therapy and an exit from dormancy have never been investigated. Here we identified the full mitochondrial genome in circulating extracellular vesicles (EVs) from patients with hormonal therapy-resistant (HTR) metastatic breast cancer. We generated xenograft models of HTR metastatic disease characterized by EVs in the peripheral circulation containing mtDNA. Moreover, these human HTR cells had acquired host-derived (murine) mtDNA promoting estrogen receptor-independent oxidative phosphorylation (OXPHOS). Functional studies identified cancer-associated fibroblast (CAF)-derived EVs (from patients and xenograft models) laden with whole genomic mtDNA as a mediator of this phenotype. Specifically, the treatment of hormone therapy (HT)-naive cells or HT-treated metabolically dormant populations with CAF-derived mtDNAhi EVs promoted an escape from metabolic quiescence and HTR disease both in vitro and in vivo. Moreover, this phenotype was associated with the acquisition of EV mtDNA, especially in cancer stem-like cells, expression of EV mtRNA, and restoration of OXPHOS. In summary, we have demonstrated that the horizontal transfer of mtDNA from EVs acts as an oncogenic signal promoting an exit from dormancy of therapy-induced cancer stem-like cells and leading to endocrine therapy resistance in OXPHOS-dependent breast cancer.

scholarly journals OR05-04 Steroid Receptor Co-Activators Complexes Cooperate with Progesterone Receptors (PR) to Reprogram Metabolic Pathways that Drive Therapy Resistant Populations in ER+ Breast Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Thu H Truong ◽  
Elizabeth Benner ◽  
Julie Hanson Ostrander ◽  
Carol A Lange
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Tumor Cell ◽  
Cell Biology ◽  
Cancer Metabolism ◽  
Progesterone Receptors ◽  
Steroid Receptor ◽  
Therapy Resistance ◽  
Cell Populations ◽  
Minority Population

Abstract Late recurrence of metastatic disease stemming from acquired therapy resistance remains a significant health burden for women with ER+ breast cancer. Disseminated ER+ tumor cell populations can remain quiescent for years to decades, and contributing factors include breast cancer stem cells (CSCs), which are non-proliferative and frequently exist as a minority population in recurrent therapy-resistant tumors. Progesterone receptors (PR) are known drivers of normal stem and breast CSCs. Our objective was to define novel signaling pathways governing cell fate transitions involved in driving therapy resistance in ER+ breast cancer. We reported that cytoplasmic complexes composed of steroid receptor (SR) co-activators, PELP1 and SRC-3, drive breast CSC outgrowth. SRC-3 knockdown abrogated PELP1-induced CSC expansion and target genes required for cell survival, suggesting an essential role for PELP1/SRC-3 complexes. PELP1 also forms a signaling and transcriptional complex with ER and PR-B. Phospho-PR species are key mediators of stemness in ER+ breast cancer models. Accordingly, PR knockdown and antiprogestins disrupted PELP1/SRC-3 complexes and blocked PELP1-induced breast CSC outgrowth. Mammary stem cell (MaSC) populations were increased in vivo in MMTV-tTA;TRE-cyto-PELP1 transgenic mice as well as in MMTV-tTA;TRE-hPR-B mice. To better understand PELP1-mediated pathways, we performed RNA-seq on MCF-7 PELP1+ models grown in tumorsphere conditions to enrich for CSC populations (ALDH+, CD44+/CD24-). Cytoplasmic PELP1-expressing cells had a different global gene profile relative to WT PELP1 (i.e. nuclear). Gene sets associated with stem cell biology, hypoxic stress, and cancer metabolism were differentially regulated, including members of the glycolytic bi-functional kinase/phosphatase PFKFB family. Seahorse metabolic phenotyping demonstrated cytoplasmic PELP1 influences metabolism by increasing both glycolysis and mitochondrial respiration. Cytoplasmic PELP1 interacted strongly with PFKFB3 and PFKFB4, and inhibition of PFKFB3 or PFKFB4 kinase activity blocked PELP1-induced tumorspheres and protein-protein interactions with SRC-3. Additionally, antiprogestin and PFKFB inhibitors were synergistic when combined with ER+ targeted therapies. These aspects of PELP1/SRC-3 biology were phenocopied in therapy resistant models (tamoxifen resistant [TamR], paclitaxel resistant [TaxR]). Together, our data suggest that PELP1, SRC-3, PR, and PFKFBs form complexes that reprogram cellular metabolism to drive breast CSC expansion. Identifying the mechanisms that regulate recurrent ER+ tumor cell populations will enable specific targeting within heterogeneous breast tumors and may lead to the development of non-ER targets that can be used in combination with endocrine treatments to overcome therapy resistance.

scholarly journals Tyrosine kinase independent actions of DDR2 in tumor cells and CAFs influence tumor invasion, migration, and metastasis

2021 ◽  
Author(s):  
Craig E. Barcus ◽  
Priscilla Y. Hwang ◽  
Vasilios Morikis ◽  
Audrey Brenot ◽  
Patrick Pence ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Tumor Invasion ◽  
Cancer Metastasis ◽  
Kinase Activity ◽  
Metastatic Breast ◽  
Tyrosine Kinase Activity

Both tumor cell-intrinsic signals and tumor cell-extrinsic signals from cells within the tumor microenvironment influence tumor cell dissemination and metastasis. The fibrillar collagen receptor tyrosine kinase discoidin domain receptor 2, DDR2, is essential for breast cancer metastasis in mouse models, and high expression of DDR2 in tumor and tumor stromal cells is strongly associated with poorer clinical outcomes. DDR2 tyrosine kinase activity was hypothesized to be required for DDR2's metastatic activity, however, inhibition of DDR2 tyrosine kinase activity, along with other RTKs, has failed to provide clinically relevant responses in metastatic patients. Here, we show that tyrosine kinase-activity independent action of DDR2 in tumor cells can support Matrigel invasion and in vivo metastasis. Paracrine actions of DDR2 in tumor cells and CAFs also support tumor invasion, migration, and lung colonization in vivo. These data suggest that tyrosine kinase independent function of DDR2 could explain failures of TKI treatment in metastatic breast cancer patients and highlight the need for alternate therapeutic strategies that inhibit both tyrosine kinase-dependent and independent actions of RTKs in the treatment of breast cancer.

The impact of HER2 phenotype of circulating tumor cells in metastatic breast cancer: a study in 107 patients

2014 ◽  
Vol 74 (S 01) ◽  
Author(s):  
M Wallwiener ◽  
AD Hartkopf ◽  
S Riethdorf ◽  
J Nees ◽  
FA Taran ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Metastatic Breast ◽  
The Impact

Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. 83-98 ◽  
Author(s):  
André De Lima Mota ◽  
Bruna Vitorasso Jardim-Perassi ◽  
Tialfi Bergamin De Castro ◽  
Jucimara Colombo ◽  
Nathália Martins Sonehara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Carbonic Anhydrases ◽  
In Vivo Models ◽  
Ca Ix ◽  
Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression. 

Sign in / Sign up

Export Citation Format

Share Document