Suppression of Nuclear Factor-κB by Glucocorticoid Receptor Blocks Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells

Fan, Ping; Siwak, Doris R.; Abderrahman, Balkees; Agboke, Fadeke A.; Yerrum, Smitha; Jordan, V. Craig

doi:10.1158/1535-7163.mct-18-1363

Cited by 22 publications

(35 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The downregulation of these enzymes in MM-MSCs would likely manifest in an altered portfolio of long-chain fatty acids available to the cell, which has been tied to both osteogenic ( 52 ) and adipogenic differentiation ( 53 ). In breast cancer cells, FADS1/2 have also been linked to inflammation via their production of arachidonic acid ( 54 ), suggesting that their suppression in MM-MSCs may be linked to an anti-inflammatory response linked to increased cytokine signaling ( 55 ).…”

Section: Discussionmentioning

confidence: 99%

Multiple Myeloma Cells Alter Adipogenesis, Increase Senescence-Related and Inflammatory Gene Transcript Expression, and Alter Metabolism in Preadipocytes

et al. 2021

View full text Add to dashboard Cite

Within the bone marrow microenvironment, mesenchymal stromal cells (MSCs) are an essential precursor to bone marrow adipocytes and osteoblasts. The balance between this progenitor pool and mature cells (adipocytes and osteoblasts) is often skewed by disease and aging. In multiple myeloma (MM), a cancer of the plasma cell that predominantly grows within the bone marrow, as well as other cancers, MSCs, preadipocytes, and adipocytes have been shown to directly support tumor cell survival and proliferation. Increasing evidence supports the idea that MM-associated MSCs are distinct from healthy MSCs, and their gene expression profiles may be predictive of myeloma patient outcomes. Here we directly investigate how MM cells affect the differentiation capacity and gene expression profiles of preadipocytes and bone marrow MSCs. Our studies reveal that MM.1S cells cause a marked decrease in lipid accumulation in differentiating 3T3-L1 cells. Also, MM.1S cells or MM.1S-conditioned media altered gene expression profiles of both 3T3-L1 and mouse bone marrow MSCs. 3T3-L1 cells exposed to MM.1S cells before adipogenic differentiation displayed gene expression changes leading to significantly altered pathways involved in steroid biosynthesis, the cell cycle, and metabolism (oxidative phosphorylation and glycolysis) after adipogenesis. MM.1S cells induced a marked increase in 3T3-L1 expression of MM-supportive genes including Il-6 and Cxcl12 (SDF1), which was confirmed in mouse MSCs by qRT-PCR, suggesting a forward-feedback mechanism. In vitro experiments revealed that indirect MM exposure prior to differentiation drives a senescent-like phenotype in differentiating MSCs, and this trend was confirmed in MM-associated MSCs compared to MSCs from normal donors. In direct co-culture, human mesenchymal stem cells (hMSCs) exposed to MM.1S, RPMI-8226, and OPM-2 prior to and during differentiation, exhibited different levels of lipid accumulation as well as secreted cytokines. Combined, our results suggest that MM cells can inhibit adipogenic differentiation while stimulating expression of the senescence associated secretory phenotype (SASP) and other pro-myeloma molecules. This study provides insight into a novel way in which MM cells manipulate their microenvironment by altering the expression of supportive cytokines and skewing the cellular diversity of the marrow.

show abstract

Section: Discussionmentioning

confidence: 99%

Multiple Myeloma Cells Alter Adipogenesis, Increase Senescence-Related and Inflammatory Gene Transcript Expression, and Alter Metabolism in Preadipocytes

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Glucocorticoids, which are given to some breast cancer patients, can also elevate blood glucose levels thus supporting glucose-dependent aerobic fermentation. In addition to elevating blood glucose, glucocorticoids can also block estrogen-induced apoptosis to further stimulate breast cancer growth (150). Hence, risk for tumor spread can be associated with accepted procedures used in breast cancer management.…”

Section: Current Standard Of Care (Soc) For Breast Cancermentioning

confidence: 99%

Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer

et al. 2020

View full text Add to dashboard Cite

Breast cancer remains as a significant cause of morbidity and mortality in women. Ultrastructural and biochemical evidence from breast biopsy tissue and cancer cells shows mitochondrial abnormalities that are incompatible with energy production through oxidative phosphorylation (OxPhos). Consequently, breast cancer, like most cancers, will become more reliant on substrate level phosphorylation (fermentation) than on oxidative phosphorylation (OxPhos) for growth consistent with the mitochondrial metabolic theory of cancer. Glucose and glutamine are the prime fermentable fuels that underlie therapy resistance and drive breast cancer growth through substrate level phosphorylation (SLP) in both the cytoplasm (Warburg effect) and the mitochondria (Q-effect), respectively. Emerging evidence indicates that ketogenic metabolic therapy (KMT) can reduce glucose availability to tumor cells while simultaneously elevating ketone bodies, a non-fermentable metabolic fuel. It is suggested that KMT would be most effective when used together with glutamine targeting. Information is reviewed for suggesting how KMT could reduce systemic inflammation and target tumor cells without causing damage to normal cells. Implementation of KMT in the clinic could improve progression free and overall survival for patients with breast cancer.

show abstract

“…In tumors resistant to LTED, estradiol-induced ER activation upregulated proinflammatory genes including IL, IFN, and arachidonic acid-related genes [ 126 ]. In LTED breast cancer cells, activation of glucocorticoid receptors blocked the estradiol-induced apoptosis via the suppressed expression and transcriptional activity of NF κ B [ 127 ].…”

Section: Molecular Events Behind the Response And Resistance Of Brmentioning

confidence: 99%

Compensatory Estrogen Signal Is Capable of DNA Repair in Antiestrogen-Responsive Cancer Cells via Activating Mutations

Suba

2020

Journal of Oncology

View full text Add to dashboard Cite

Cancer cells are embarrassed human cells exhibiting the remnants of same mechanisms for DNA stabilization like patients have in their healthy cells. Antiestrogens target the liganded activation of ERs, which is the principal means of genomic regulation in both patients and their tumors. The artificial blockade of liganded ER activation is an emergency situation promoting strong compensatory actions even in cancer cells. When tumor cells are capable of an appropriate upregulation of ER signaling resulting in DNA repair, a tumor response may be detected. In contrast, when ER signaling is completely inhibited, tumor cells show unrestrained proliferation, and tumor growth may be observed. The laboratory investigations of genomic mechanisms in antiestrogen-responsive and antiestrogen-unresponsive tumor cells have considerably enhanced our knowledge regarding the principal regulatory capacity of estrogen signaling. In antiestrogen-responsive tumor cells, a compensatory increased expression and liganded activation of estrogen receptors (ERs) result in an apoptotic death. Conversely, in antiestrogen resistant tumors exhibiting a complete blockade of liganded ER activation, a compensatory effort for unliganded ER activation is characteristic, conferred by the increased expression and activity of growth factor receptors. However, even extreme unliganded ER activation is incapable of DNA restoration when the liganded ER activation is completely blocked. Researchers mistakenly suspect even today that in tumors growing under antiestrogen treatment, the increased unliganded activation of estrogen receptor via activating mutations is an aggressive survival technique, whilst it is a compensatory effort against the blockade of liganded ER activation. The capacity of liganded ERs for genome modification in emergency states provides possibilities for estrogen/ER use in medical practice including cancer cure.

show abstract

Suppression of Nuclear Factor-κB by Glucocorticoid Receptor Blocks Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells

Cited by 22 publications

References 53 publications

Multiple Myeloma Cells Alter Adipogenesis, Increase Senescence-Related and Inflammatory Gene Transcript Expression, and Alter Metabolism in Preadipocytes

Multiple Myeloma Cells Alter Adipogenesis, Increase Senescence-Related and Inflammatory Gene Transcript Expression, and Alter Metabolism in Preadipocytes

Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer

Compensatory Estrogen Signal Is Capable of DNA Repair in Antiestrogen-Responsive Cancer Cells via Activating Mutations

Contact Info

Product

Resources

About