Abstract P2-19-01: Modulating Response to Phosphoinositol-3-Kinase/mTOR Inhibition in ER Positive Breast Cancer Cell Lines after Acquired Resistance to Estrogen Deprivation

2010 ◽  
Author(s):  
CG Sanchez ◽  
RJ Crowder ◽  
C Phommaly ◽  
MJ. Ellis
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Breast Cancer Cell ◽  
Acquired Resistance ◽  
Breast Cancer Cell Lines ◽  
Estrogen Deprivation ◽  
Mtor Inhibition ◽  
Er Positive ◽  
Positive Breast Cancer Cell ◽  
Positive Breast Cancer

scholarly journals Deciphering the Molecular Mechanisms Sustaining the Estrogenic Activity of the Two Major Dietary Compounds Zearalenone and Apigenin in ER-Positive Breast Cancer Cell Lines

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 237 ◽  
Author(s):  
Sylvain Lecomte ◽  
Florence Demay ◽  
Thu Ha Pham ◽  
Solenn Moulis ◽  
Théo Efstathiou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Differential Effect ◽  
Molecular Mechanisms ◽  
Breast Cancer Cell Lines ◽  
Er Positive ◽  
Positive Breast Cancer Cell ◽  
Positive Breast Cancer

The flavone apigenin and the mycotoxin zearalenone are two major compounds found in the human diet which bind estrogen receptors (ERs), and therefore influence ER activity. However, the underlying mechanisms are not well known. To unravel the molecular mechanisms that could explain the differential effect of zearalenone and apigenin on ER-positive breast cancer cell proliferation, gene-reporter assays, chromatin immunoprecipitation (ChIP) experiments, proliferation assays and transcriptomic analysis were performed. We found that zearalenone and apigenin transactivated ERs and promoted the expression of estradiol (E2)-responsive genes. However, zearalenone clearly enhanced cellular proliferation, while apigenin appeared to be antiestrogenic in the presence of E2 in both ER-positive breast cancer cell lines, MCF-7 and T47D. The transcriptomic analysis showed that both compounds regulate gene expression in the same way, but with differences in intensity. Two major sets of genes were identified; one set was linked to the cell cycle and the other set was linked to stress response and growth arrest. Our results show that the transcription dynamics in gene regulation induced by apigenin were somehow different with zearalenone and E2 and may explain the differential effect of these compounds on the phenotype of the breast cancer cell. Together, our results confirmed the potential health benefit effect of apigenin, while zearalenone appeared to be a true endocrine-disrupting compound.

scholarly journals The Novel Oral mTORC1/2 Inhibitor TAK-228 Reverses Trastuzumab Resistance in HER2-Positive Breast Cancer Models

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2778
Author(s):  
Marta Sanz-Álvarez ◽  
Ester Martín-Aparicio ◽  
Melani Luque ◽  
Sandra Zazo ◽  
Javier Martínez-Useros ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Breast Cancer Cell ◽  
Acquired Resistance ◽  
Mtor Inhibitors ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer Cell ◽  
Positive Breast Cancer

The use of anti-HER2 therapies has significantly improved clinical outcome in patients with HER2-positive breast cancer, yet a substantial proportion of patients acquire resistance after a period of treatment. The PI3K/AKT/mTOR pathway is a good target for drug development, due to its involvement in HER2-mediated signalling and in the emergence of resistance to anti-HER2 therapies, such as trastuzumab. This study evaluates the activity of three different PI3K/AKT/mTOR inhibitors, i.e., BEZ235, everolimus and TAK-228 in vitro, in a panel of HER2-positive breast cancer cell lines with primary and acquired resistance to trastuzumab. We assess the antiproliferative effect and PI3K/AKT/mTOR inhibitory capability of BEZ235, everolimus and TAK-228 alone, and in combination with trastuzumab. Dual blockade with trastuzumab and TAK-228 was superior in reversing the acquired resistance in all the cell lines. Subsequently, we analyse the effects of TAK-228 in combination with trastuzumab on the cell cycle and found a significant increase in G0/G1 arrest in most cell lines. Likewise, the combination of both drugs induced a significant increase in apoptosis. Collectively, these experiments support the combination of trastuzumab with PI3K/AKT/mTOR inhibitors as a potential strategy for inhibiting the proliferation of HER2-positive breast cancer cell lines that show resistance to trastuzumab.

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