scholarly journals Anti-proliferative effect of estrogen in breast cancer cells that re-express ERα is mediated by aberrant regulation of cell cycle genes

2005 ◽  
Vol 34 (2) ◽  
pp. 535-551 ◽  
Author(s):  
J G Moggs ◽  
T C Murphy ◽  
F L Lim ◽  
D J Moore ◽  
R Stuckey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cyclin B1 ◽  
Tumour Suppressor Genes ◽  
Cell Cycle Regulators ◽  
Adenoviral Infection ◽  
Promote Cell Proliferation ◽  
Er Positive

Estrogen receptor (ER)-negative breast carcinomas do not respond to hormone therapy, making their effective treatment very difficult. The re-expression of ERα in ER-negative MDA-MB-231 breast cancer cells has been used as a model system, in which hormone-dependent responses can be restored. Paradoxically, in contrast to the mitogenic activity of 17β-estradiol (E2) in ER-positive breast cancer cells, E2 suppresses proliferation in ER-negative breast cancer cells in which ERα has been re-expressed. We have used global gene expression profiling to investigate the mechanism by which E2 suppresses proliferation in MDA-MB-231 cells that express ERα through adenoviral infection. We show that a number of genes known to promote cell proliferation and survival are repressed by E2 in these cells. These include genes encoding the anti-apoptosis factor SURVIVIN, positive cell cycle regulators (CDC2, CYCLIN B1, CYCLIN B2, CYCLIN G1, CHK1, BUB3, STK6, SKB1, CSE1 L) and chromosome replication proteins (MCM2, MCM3, FEN1, RRM2, TOP2A, RFC1). In parallel, E2-induced the expression of the negative cell cycle regulators KIP2 and QUIESCIN Q6, and the tumour-suppressor genes E-CADHERIN and NBL1. Strikingly, the expression of several of these genes is regulated in the opposite direction by E2 compared with their regulation in ER-positive MCF-7 cells. Together, these data suggest a mechanism for the E2-dependent suppression of proliferation in ER-negative breast cancer cells into which ERα has been reintroduced.

scholarly journals Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway

Oncogene ◽  
2009 ◽  
Vol 29 (2) ◽  
pp. 285-296 ◽  
Author(s):  
N H Thoennissen ◽  
J O'Kelly ◽  
D Lu ◽  
G B Iwanski ◽  
D T La ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cycle Arrest ◽  
Er Positive ◽  
Her 2

scholarly journals Adipocytes Under Obese-Like Conditions Change Cell Cycle Distribution and Phosphorylation Profiles of Breast Cancer Cells: The Adipokine Receptor CAP1 Matters

2021 ◽  
Vol 11 ◽  
Author(s):  
Malin Bergqvist ◽  
Karin Elebro ◽  
Signe Borgquist ◽  
Ann H. Rosendahl
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Cell Cycle Distribution ◽  
Antibody Array ◽  
Er Positive ◽  
Metabolic Conditions

BackgroundObesity and associated metabolic conditions impact adipocyte functionality with potential consequences for breast cancer risk and prognosis, but contributing mechanisms remain to be understood. The adipokine receptor adenylyl cyclase-associated protein-1 (CAP1) has been implicated in the progression of breast cancer, but results are conflicting and the underlying molecular mechanisms are still unknown. In this study, molecular and cellular effects in breast cancer cells by stimulation of adipocytes under normal or obese-like conditions, and potential involvement of CAP1, were assessed.Material and MethodsEstrogen receptor (ER)-positive T47D and ER-negative MDA-MB-231 breast cancer cells were exposed to adipocyte-secretome from adipocytes placed under pressures mimicking normal and obese-like metabolic conditions. Changes in phosphorylated kinase proteins and related biological pathways were assessed by phospho-antibody array and PANTHER analysis, cell proliferation were investigated through sulforhodamine B, cell cycle distribution by flow cytometry. Functional effects of CAP1 were subsequently examined following small interfering (si)RNA-mediated knockdown.ResultsProtein phosphorylations involved in important biological processes were enriched in T47D breast cancer cells in response to adipocyte secretome from obese-like compared with normal conditions. The obesity-associated adipocyte secretome further stimulated cell proliferation and a shift from cell cycle G1-phase to S- and G2/M-phase was observed. Silencing of CAP1 decreased cell proliferation in both T47D and MDA-MB-231 cells, and reduced the obesity-associated secretome-induction of phosphoproteins involved in cell proliferation pathways.ConclusionsThese results indicate that the adipocyte secretome and CAP1 are mechanistically important for the proliferation of both ER-positive and ER-negative breast cancer cells, and potential signaling mediators were identified. These studies provide biological insight into how obesity-associated factors could affect breast cancer.

scholarly journals The mechanisms involved in the resistance of estrogen receptor-positive breast cancer cells to palbociclib are multiple and change over time

2021 ◽  
Author(s):  
Mayu Ono ◽  
Takaaki Oba ◽  
Tomohiro Shibata ◽  
Ken-ichi Ito
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Copy Number ◽  
Breast Cancer Cells ◽  
Copy Number Alterations ◽  
Altered Expression ◽  
Er Positive ◽  
Positive Breast Cancer

Abstract Purpose Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are widely used for the treatment of advanced estrogen receptor (ER)-positive breast cancer. To develop a treatment strategy for cancers resistant to CDK4/6 inhibitors, here, we established palbociclib-resistant sublines and analyzed their resistance mechanisms. Methods Palbociclib-resistant sublines were established from T47D and MCF7 cells. Sensitivity to other drugs was assessed via the WST assay. Altered expression/phosphorylation of proteins related to signal transduction and cell cycle regulation was examined using western blotting. Copy number alterations and mutations in the retinoblastoma (RB1) gene were also analyzed. Results Although an increase in CDK6 and decrease in retinoblastoma protein (Rb) expression/phosphorylation were commonly observed in the resistant sublines, changes in other cell cycle-related proteins were heterogeneous. Upon extended exposure to palbociclib, the expression/phosphorylation of these proteins became altered, and the long-term removal of palbociclib did not restore the Rb expression/phosphorylation patterns. Consistently a copy number decrease, as well as RB1 mutations were detected. Moreover, although the resistant sublines exhibited cross-resistance to abemaciclib, their response to dinaciclib was the same as that of wild-type cells. Of note, the cell line exhibiting increased mTOR phosphorylation also showed a higher sensitivity to everolimus. However, the sensitivity to chemotherapeutic agents was unchanged in palbociclib-resistant sublines. Conclusion ER-positive breast cancer cells use multiple molecular mechanisms to survive in the presence of palbociclib, suggesting that targeting activated proteins may be an effective strategy to overcome resistance. Additionally, palbociclib monotherapy induces mutations and copy number alterations in the RB1 gene.

scholarly journals Chaperonin-Containing TCP1 Complex (CCT) Promotes Breast Cancer Growth Through Correlations With Key Cell Cycle Regulators

2021 ◽  
Vol 11 ◽  
Author(s):  
Heba Ghozlan ◽  
Adrian Showalter ◽  
Eunkyung Lee ◽  
Xiang Zhu ◽  
Annette R. Khaled
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Single Agent ◽  
Three Dimensional ◽  
Cell Cycle Regulators ◽  
Luminal A ◽  
Genomic Amplification ◽  
Cell Cycle Inhibition

Uncontrolled proliferation as a result of dysregulated cell cycling is one of the hallmarks of cancer. Therapeutically targeting pathways that control the cell cycle would improve patient outcomes. However, the development of drug resistance and a limited number of inhibitors that target multiple cell cycle modulators are challenges that impede stopping the deregulated growth that leads to malignancy. To advance the discovery of new druggable targets for cell cycle inhibition, we investigated the role of Chaperonin-Containing TCP1 (CCT or TRiC) in breast cancer cells. CCT, a type II chaperonin, is a multi-subunit protein-folding complex that interacts with many oncoproteins and mutant tumor suppressors. CCT subunits are highly expressed in a number of cancers, including breast cancer. We found that expression of one of the CCT subunits, CCT2, inversely correlates with breast cancer patient survival and is subject to copy number alterations through genomic amplification. To investigate a role for CCT2 in the regulation of the cell cycle, we expressed an exogenous CCT2-FLAG construct in T47D and MCF7 luminal A breast cancer cells and examined cell proliferation under conditions of two-dimensional (2D) monolayer and three-dimensional (3D) spheroid cultures. Exogenous CCT2 increased the proliferation of cancer cells, resulting in larger and multiple spheroids as compared to control cells. CCT2-expressing cells were also able to undergo spheroid growth reversal, re-attaching, and resuming growth in 2D cultures. Such cells gained anchorage-independent growth. CCT2 expression in cells correlated with increased expression of MYC, especially in spheroid cultures, and other cell cycle regulators like CCND1 and CDK2, indicative of a novel activity that could contribute to the increase in cell growth. Statistically significant correlations between CCT2, MYC, and CCND1 were shown. Since CCT2 is located on chromosome 12q15, an amplicon frequently found in soft tissue cancers as well as breast cancer, CCT2 may have the basic characteristics of an oncogene. Our findings suggest that CCT2 could be an essential driver of cell division that may be a node through which pathways involving MYC, cyclin D1 and other proliferative factors could converge. Hence the therapeutic inhibition of CCT2 may have the potential to achieve multi-target inhibition, overcoming the limitations associated with single agent inhibitors.

scholarly journals Induction of Apoptosis and Regulation of MicroRNA Expression by (2E,6E)-2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) Treatment on MCF-7 Breast Cancer Cells

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1277
Author(s):  
Swee Keong Yeap ◽  
Norlaily Mohd Ali ◽  
Muhammad Nadeem Akhtar ◽  
Nursyamirah Abd Razak ◽  
Zhi Xiong Chong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
M Cell ◽  
Cytotoxic Effects ◽  
Er Positive ◽  
Mcf 7

(2E,6E)-2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) is a synthetic curcumin analogue, which has been reported to possess anti-tumor, anti-metastatic, and anti-invasion properties on estrogen receptor (ER) negative breast cancer cells in vitro and in vivo. However, the cytotoxic effects of BHMC on ER positive breast cancer cells were not widely reported. This study was aimed to investigate the cytotoxic potential of BHMC on MCF-7 cells using cell viability, cell cycle, and apoptotic assays. Besides, microarray and quantitative polymerase chain reaction (qPCR) were performed to identify the list of miRNAs and genes, which could be dysregulated following BHMC treatment. The current study discovered that BHMC exhibits selective cytotoxic effects on ER positive MCF-7 cells as compared to ER negative MDA-MB-231 cells and normal breast cells, MCF-10A. BHMC was shown to promote G2/M cell cycle arrest and apoptosis in MCF-7 cells. Microarray and qPCR analysis demonstrated that BHMC treatment would upregulate several miRNAs like miR-3195 and miR-30a-3p and downregulate miRNAs such as miR-6813-5p and miR-6132 in MCF-7 cells. Besides, BHMC administration was also found to downregulate few tumor-promoting genes like VEGF and SNAIL in MCF-7. In conclusion, BHMC induced apoptosis in the MCF-7 cells by altering the expressions of apoptotic-regulating miRNAs and associated genes.

scholarly journals Treatment with DHA Modifies the Response of MDA-MB-231 Breast Cancer Cells and Tumors from nu/nu Mice to Doxorubicin through Apoptosis and Cell Cycle Arrest

2019 ◽  
Vol 149 (1) ◽  
pp. 46-56 ◽  
Author(s):  
Marnie Newell ◽  
Miranda Brun ◽  
Catherine J Field
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cyclin B1 ◽  
Cell Cycle Genes ◽  
Cycle Arrest ◽  
And Function

ABSTRACT Background Docosahexaenoic acid (DHA) has been shown to reduce growth of breast cancer cells in vitro and in vivo; it may also benefit the action of cytotoxic cancer drugs. The mechanisms for these observations are not completely understood. Objectives We sought to explore how pretreatment of MDA-MB-231 breast cancer cells with DHA alters gene expression with doxorubicin (DOX) treatment and confirm that feeding DHA to tumor-bearing nu/nu mice improves the efficacy of DOX. Methods MDA-MB-231 cells were subjected to 4 conditions: a control mixture of 40 μM linoleic and 40 μM oleic acid (OALA), DHA (60 μM plus OALA), OALA DOX (0.41 μM), or DHA DOX (plus OALA) and assessed for effects on viability and function. Female nu/nu mice (6 wk old) bearing MDA-MB-231 tumors were randomly assigned to a nutritionally complete diet (20 g ± 2.8 g DHA/100 g diet) containing a polyunsaturated:saturated fat ratio of 0.5, with or without injections 2 times/wk of 5 mg DOX/kg for 4 wk. Results Microarray and protein analysis indicated that DHA DOX cells, compared with OALA DOX, had upregulated expression of apoptosis genes, Caspase-10 (1.3-fold), Caspase-9 (1.4-fold), and Receptor (TNFRSF)-interacting serine-threonine kinase 1 (RIPK1) (1.2-fold), while downregulating cell cycle genes, Cyclin B1 (−2.1-fold), WEE1 (−1.6-fold), and cell division cycle 25 homolog C (CDC25C) (−1.8-fold) (P < 0.05). DHA DOX–treated mice had 50% smaller tumors than control mice (P < 0.05). Analysis of proapoptotic proteins from tumors of DHA DOX mice showed increased Caspase-10 (by 68%) and BH3 interacting domain death agonist (Bid) (by 50%), decreased B-cell CLL/lymphoma 2 (BCL2) (by 24%), and decreased cell cycle proteins Cyclin B1 and Cdc25c (both by 42%), compared with control mice (P < 0.05). Conclusions Supplementation with DHA facilitates the action of DOX in MDA-MB-231 cells and in nu/nu mice, which may occur via amplification of the effect of DOX on apoptosis and cell cycle genes.

scholarly journals Piperlongumine Induces Cell Cycle Arrest via Reactive Oxygen Species Accumulation and IKKβ Suppression in Human Breast Cancer Cells

Antioxidants ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 553 ◽  
Author(s):  
Chang Hee Jeong ◽  
Haram Ryu ◽  
Do Hyun Kim ◽  
Wei Nee Cheng ◽  
Jee Eun Yoon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Mrna Levels ◽  
Cycle Arrest ◽  
Anticancer Effects ◽  
Er Positive ◽  
And Migration ◽  
Positive Breast Cancer

Piperlongumine (PL), a natural product derived from long pepper (Piper longum L.), is known to exhibit anticancer effects. However, the effect of PL on cell cycle-regulatory proteins in estrogen receptor (ER)-positive breast cancer cells is unclear. Therefore, we investigated whether PL can modulate the growth of ER-positive breast cancer cell line, MCF-7. We found that PL decreased MCF-7 cell proliferation and migration. Flow cytometric analysis demonstrated that PL induced G2/M phase cell cycle arrest. Moreover, PL significantly modulated the mRNA levels of cyclins B1 and D1, cyclin-dependent kinases 1, 4, and 6, and proliferating cell nuclear antigen. PL induced intracellular reactive oxygen species (hydrogen peroxide) accumulation and glutathione depletion. PL-mediated inhibition of IKKβ expression decreased nuclear translocation of NF-κB p65. Furthermore, PL significantly increased p21 mRNA levels. In conclusion, our data suggest that PL exerts anticancer effects in ER-positive breast cancer cells by inhibiting cell proliferation and migration via ROS accumulation and IKKβ suppression.

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