scholarly journals Adenomatous Polyposis Coli loss controls cell cycle regulators and response to paclitaxel in MDA-MB-157 metaplastic breast cancer cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255738
Author(s):  
Emily M. Astarita ◽  
Sara M. Maloney ◽  
Camden A. Hoover ◽  
Bronwyn J. Berkeley ◽  
Monica K. VanKlompenberg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Adenomatous Polyposis Coli ◽  
Cyclin B1 ◽  
Cell Cycle Analysis ◽  
Specific Cell ◽  
Breast Cancers ◽  
Cell Cycle Regulators ◽  
Adenomatous Polyposis ◽  
Polyposis Coli

Adenomatous Polyposis Coli (APC) is lost in approximately 70% of sporadic breast cancers, with an inclination towards triple negative breast cancer (TNBC). TNBC is treated with traditional chemotherapy, such as paclitaxel (PTX); however, tumors often develop drug resistance. We previously created APC knockdown cells (APC shRNA1) using the human TNBC cells, MDA-MB-157, and showed that APC loss induces PTX resistance. To understand the mechanisms behind APC-mediated PTX response, we performed cell cycle analysis and analyzed cell cycle related proteins. Cell cycle analysis indicated increased G2/M population in both PTX-treated APC shRNA1 and parental cells, suggesting that APC expression does not alter PTX-induced G2/M arrest. We further studied the subcellular localization of the G2/M transition proteins, cyclin B1 and CDK1. The APC shRNA1 cells had increased CDK1, which was preferentially localized to the cytoplasm, and increased baseline CDK6. RNA-sequencing was performed to gain a global understanding of changes downstream of APC loss and identified a broad mis-regulation of cell cycle-related genes in APC shRNA1 cells. Our studies are the first to show an interaction between APC and taxane response in breast cancer. The implications include designing combination therapy to re-sensitize APC-mutant breast cancers to taxanes using the specific cell cycle alterations.

scholarly journals Adenomatous Polyposis Coli Loss Controls Cell Cycle Regulators and Response to Paclitaxel

2020 ◽  
Author(s):  
Emily M. Astarita ◽  
Camden A. Hoover ◽  
Sara M. Maloney ◽  
T. Murlidharan Nair ◽  
Jenifer R. Prosperi
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Adenomatous Polyposis Coli ◽  
Cyclin B1 ◽  
Cell Cycle Analysis ◽  
Specific Cell ◽  
Breast Cancers ◽  
Cell Cycle Regulators ◽  
Adenomatous Polyposis ◽  
Polyposis Coli

AbstractAdenomatous Polyposis Coli (APC) is lost in approximately 70% of sporadic breast cancers, with an inclination towards triple negative breast cancer (TNBC). TNBC is treated with traditional chemotherapy, such as paclitaxel (PTX); however, tumors often develop drug resistance. We previously created APC knockdown cells (APC shRNA1) using the human TNBC cells, MDA-MB-157, and showed that APC loss induces PTX resistance. To understand the mechanisms behind APC-mediated PTX response, we performed cell cycle analysis and analyzed cell cycle related proteins. Cell cycle analysis indicated increased G2/M population in PTX-treated APC shRNA1 cells compared to PTX-treated controls, suggesting that APC expression does not alter PTX-induced G2/M arrest. We further studied the subcellular localization of the G2/M transition proteins, cyclin B1 and CDK1. The APC shRNA1 cells had increased CDK1, which was preferentially localized to the cytoplasm, and increased CDK6. RNA-sequencing was performed to gain a global understanding of changes downstream of APC loss and identified a broad mis-regulation of cell cycle-related genes in APC shRNA1 cells. Our studies are the first to show an interaction between APC and taxane response in breast cancer. The implications include designing combination therapy to re-sensitize APC-mutant breast cancers to taxanes using the specific cell cycle alterations.

scholarly journals Adenomatous Polyposis Coli and Ras Association Domain Family 1A Gene Methylation in Breast Cancer Patients

2007 ◽  
Vol 10 (2) ◽  
pp. 120
Author(s):  
Il-kyung Park ◽  
Jee-Soo Yim ◽  
Yu-Mi Ra ◽  
Dae-gyung Ko ◽  
In-seok Choi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Adenomatous Polyposis Coli ◽  
Adenomatous Polyposis ◽  
Breast Cancer Patients ◽  
Polyposis Coli ◽  
Domain Family ◽  
Gene Methylation

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.

MUC1 can interact with adenomatous polyposis coli in breast cancer

2004 ◽  
Vol 316 (2) ◽  
pp. 364-369 ◽  
Author(s):  
Christine L Hattrup ◽  
Julia Fernandez-Rodriguez ◽  
Joyce A Schroeder ◽  
Gunnar C Hansson ◽  
Sandra J Gendler
Keyword(s):  
Breast Cancer ◽  
Adenomatous Polyposis Coli ◽  
Adenomatous Polyposis ◽  
Polyposis Coli

scholarly journals Aberrant methylation of the Adenomatous Polyposis Coli (APC) gene promoter is associated with the inflammatory breast cancer phenotype

2008 ◽  
Vol 99 (10) ◽  
pp. 1735-1742 ◽  
Author(s):  
I Van der Auwera ◽  
S J Van Laere ◽  
S M Van den Bosch ◽  
G G Van den Eynden ◽  
B X Trinh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adenomatous Polyposis Coli ◽  
Inflammatory Breast Cancer ◽  
Gene Promoter ◽  
Apc Gene ◽  
Aberrant Methylation ◽  
Adenomatous Polyposis ◽  
Polyposis Coli ◽  
Cancer Phenotype

scholarly journals BCL-XL blockage in TNBC models confers vulnerability to inhibition of specific cell cycle regulators

2021 ◽  
Author(s):  
Olivier Castellanet ◽  
Fahmida Ahmad ◽  
Yaron Vinik ◽  
Gordon B Mills ◽  
Bianca H Habermann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Human Breast Cancer ◽  
Specific Cell ◽  
Cell Cycle Regulators ◽  
Human Breast ◽  
Primary Resistance ◽  
Western Blots ◽  
Expression Levels ◽  
Cellular Localisation

Cell cycle regulators are frequently altered in Triple-Negative Breast Cancer (TNBC). Emerging agents targeting these signals offer the possibility to design new combinatorial therapies. However, preclinical models that recapitulate TNBC primary resistance and heterogeneity are essential to evaluate the potency of these combined treatments. Methods: Bioinformatic processing of human breast cancer datasets was used to analyse correlations between expression levels of cell cycle regulators and patient survival outcome. The MMTV-R26Met mouse model of TNBC resistance and heterogeneity was employed to analyse expression and targeting vulnerability of cell cycle regulators in the presence of BCL-XL blockage. Robustness of outcomes and selectivity was further explored using a panel of human breast cancer cells. Alterations of protein expression, phosphorylation, and/or cellular localisation were analysed by western blots, reverse phase protein array, and immunocytochemistry. Bioinformatics was performed to highlight drug's mechanisms of action. Results: We report that high expression levels of BCL-XL and specific cell cycle regulators correlate with poor survival outcomes of TNBC patients. Blockage of BCL-XL confers vulnerability to drugs targeting CDK1/2/4, but not FOXM1, CDK4/6, Aurora A and Aurora B, to all MMTV-R26Met and human TNBC cell lines tested. Mechanistically, we show that, co-targeting of BCL-XL and CDK1/2/4 synergistically inhibited cell growth by combinatorial depletion of survival and RTK/AKT signals, and concomitantly restoring FOXO3a tumour suppression actions. This was accompanied by an accumulation of DNA damage and consequently apoptosis. Conclusions: Our studies illustrate the possibility to exploit the vulnerability of TNBC cells to CDK1/2/4 inhibition by targeting BCL-XL. Moreover, they underline that specificity matters in targeting cell cycle regulators for combinatorial anticancer therapies.

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