scholarly journals PI3K-based molecular signatures link high PI3K pathway activity with low ER levels in ER+breast cancer

2010 ◽  
Vol 7 (6) ◽  
pp. 819-821 ◽  
Author(s):  
Alex Sanchez ◽  
Josep Villanueva
Keyword(s):  
Breast Cancer ◽  
Pi3k Pathway ◽  
Molecular Signatures ◽  
Pathway Activity

scholarly journals Heterogeneity in signaling pathway activity within primary and between primary and metastatic breast cancer

2020 ◽  
Author(s):  
Márcia A. Inda ◽  
Paul van Swinderen ◽  
Anne van Brussel ◽  
Cathy B. Moelans ◽  
Wim Verhaegh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Signaling Pathway ◽  
Metastatic Breast ◽  
Pi3k Pathway ◽  
Pathway Activity ◽  
Micro Scale ◽  
Scale Heterogeneity ◽  
Macro Scale ◽  
Heterogeneity Analysis

AbstractBackgroundTargeted drug treatment aims to block tumor driving signaling pathways, and is generally based on analysis of one primary tumor (PT) biopsy. Phenotypic heterogeneity within primary and between primary and metastatic lesions was investigated.MethodsActivity of androgen and estrogen receptor, PI3K-FOXO, Hedgehog, TGFβ, and Wnt signaling pathways was measured in breast cancer samples using a novel mRNA-based assay platform. Macro-scale heterogeneity analysis was performed on multiple spatially distributed PT tissue blocks from 17 luminal A-like, 9 luminal B-like, and 9 ER-negative primary breast cancers; micro-scale heterogeneity analysis was performed on four “quadrant” samples of a single tissue block of respectively 9, 4, and 4 matched PT. Samples from 6 PT with matched lymph node (LN, n=23) and 9 PT with distant metastatic sites (DS, n=12) were analyzed. Statistical variance analysis was performed with linear mixed models. A “checkerboard” model was introduced to explain the observed heterogeneity in PT.ResultsWithin PT, macro-scale heterogeneity in signaling pathway activity was similar to micro-scale heterogeneity, with a possible exception of the PI3K pathway. Variation was significantly higher on microscale for Hedgehog and TGFβ pathways. While pathway activity scores correlated significantly between different locations in the PT, positive correlations decreased between PT and LN, and even more between PT and DS metastases, including the emergence of a negative correlation for the ER pathway.ConclusionWith a possible exception of the PI3K pathway, variation in signaling pathway activity within a single PT tissue block was generally representative for the whole PT, but not for DS or LN metastases. The higher variation in TGFβ and HH pathway activity on microscale suggested the presence of multiple small cancer cell clones. While analysis of multiple sub-samples of a single biopsy block may be sufficient to predict PT response to some targeted therapies, such as hormonal therapy, metastatic breast cancer treatment requires analysis of metastatic biopsies. The findings on phenotypic intra-tumor heterogeneity are compatible with currently emerging ideas on a Big Bang type of cancer evolution.

scholarly journals Relationship of PIK3CA Mutation and PI3K Pathway Activity with Antiproliferative Response to Anastrozole in Er+ Breast Cancer

2013 ◽  
Vol 24 ◽  
pp. iii29 ◽  
Author(s):  
C. Segal ◽  
E. Lopez-Knowles ◽  
V. Patel ◽  
I. Garcia-Murillas ◽  
N. Turner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Pik3ca Mutation ◽  
Pi3k Pathway ◽  
Pathway Activity ◽  
Relationship Of

scholarly journals Heterogeneity in Signaling Pathway Activity within Primary and between Primary and Metastatic Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1345
Author(s):  
Márcia A. Inda ◽  
Paul van Swinderen ◽  
Anne van Brussel ◽  
Cathy B. Moelans ◽  
Wim Verhaegh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Tumor Heterogeneity ◽  
Metastatic Breast ◽  
Big Bang ◽  
Pi3k Pathway ◽  
Pathway Activity ◽  
Micro Scale ◽  
Macro Scale ◽  
Scale Variation

Targeted therapy aims to block tumor-driving signaling pathways and is generally based on analysis of one primary tumor (PT) biopsy. Tumor heterogeneity within PT and between PT and metastatic breast lesions may, however, impact the effect of a chosen therapy. Whereas studies are available that investigate genetic heterogeneity, we present results on phenotypic heterogeneity by analyzing the variation in the functional activity of signal transduction pathways, using an earlier developed platform to measure such activity from mRNA measurements of pathways’ direct target genes. Statistical analysis comparing macro-scale variation in pathway activity on up to five spatially distributed PT tissue blocks (n = 35), to micro-scale variation in activity on four adjacent samples of a single PT tissue block (n = 17), showed that macro-scale variation was not larger than micro-scale variation, except possibly for the PI3K pathway. Simulations using a “checkerboard clone-size” model showed that multiple small clones could explain the higher micro-scale variation in activity found for the TGFβ and Hedgehog pathways, and that intermediate/large clones could explain the possibly higher macro-scale variation of the PI3K pathway. While within PT, pathway activities presented a highly positive correlation, correlations weakened between PT and lymph node metastases (n = 9), becoming even worse for PT and distant metastases (n = 9), including a negative correlation for the ER pathway. While analysis of multiple sub-samples of a single biopsy may be sufficient to predict PT response to targeted therapies, metastatic breast cancer treatment prediction requires analysis of metastatic biopsies. Our findings on phenotypic intra-tumor heterogeneity are compatible with emerging ideas on a Big Bang type of cancer evolution in which macro-scale heterogeneity appears not dominant.

scholarly journals Relationship between stemness and transcriptionally-inferred PI3K activity in human breast cancer

2020 ◽  
Author(s):  
Ralitsa R. Madsen ◽  
Oscar M. Rueda ◽  
Xavier Robin ◽  
Carlos Caldas ◽  
Robert K. Semple ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Pi3k Pathway ◽  
Activity Score ◽  
Breast Cancers ◽  
Mutation Status ◽  
Pathway Activity ◽  
Molecular Tests ◽  
Pi3k Activity ◽  
Mutational Status ◽  
Per Se

ABSTRACTThe development of reliable, prognostically informative molecular tests to direct targeted cancer therapy is a major challenge. In 2019, the PI3Kα inhibitor alpelisib was approved for the treatment of advanced breast cancer, in combination with the oestrogen receptor degrader fulvestrant, with some evidence for improved therapeutic response in patients classified as having tumours which were positive for mutation in PIK3CA, the gene encoding PI3Kα. Using human pluripotent stem cells, we recently demonstrated that the PIK3CAH1047R oncogenic hotspot variant shows marked PIK3CA allele dose-dependent activation of PI3K signalling and induction of self-sustained stemness. Together with recent discoveries of multi-copy and double-cis PIK3CA mutations in human cancers, this calls for a re-evaluation of the PIK3CA genotype-phenotype relationship and the current use of binary stratification by PIK3CA mutation status. Using computational analyses, we thus investigated the relationship between PIK3CA mutational status, PI3K activity/signalling strength and stemness. Stemness and PI3K activity scores were calculated using open-source methods and well-established transcriptional signatures. We report that a high PI3K pathway activity score, but not the presence of PIK3CA mutation per se, predicts increased breast cancer dedifferentiation and higher stemness, correlating with reduced overall survival. Our data (1) corroborate reports that the presence of a PIK3CA mutation per se does not predict high PI3K pathway activation or poor prognosis; (2) suggest that stratification of breast cancer for PI3K-based therapy might benefit from the use of a PI3K pathway activity score rather than binary PIK3CA mutation status alone; (3) suggest that combination of PI3K pathway inhibitors with differentiation-promoting treatments warrants evaluation in aggressive breast cancers with high PI3K activity and stemness scores.

Effect of eribulin on cell growth and PI3K pathway activity with and without RAD001 in triple-negative and HER2-expressing breast cancer.

2013 ◽  
Vol 31 (26_suppl) ◽  
pp. 173-173 ◽  
Author(s):  
David Luyimbazi ◽  
Thehang H. Luu ◽  
Quanhua Xing ◽  
Jin Yan ◽  
Dylan Tully ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Pi3k Pathway ◽  
Western Blots ◽  
Pathway Activity ◽  
Phosphorylated Akt

173 Background: Patients with triple-negative breast cancer have high levels of Akt expression and activation of the PI3K-mTOR pathway. Eribulin is a microtubule-targeting agent with benefits in treating refractory triple negative disease. Our objective was to evaluate its efficacy in inhibiting PI3K pathway activity and cell growth both alone and in combination with the mTOR inhibitor RAD001. Methods: MDA468, BT549 and SKBR3 breast cancer cell lines were used for this study. MTT assays were used to assess growth inhibition after 72 hour treatment with eribulin alone and in combination with RAD001. Combination indices (CI) generated by Chou-Talalay plots were used to quantify synergy. Western blots were used to evaluate the expression of phosphorylated Akt-Ser473 (pAkt) and S6K1 after 24 hours of treatment with both agents. Results: Both MDA468 and SKBR3 cells treated with eribulin in varying concentrations showed inhibition of pAkt expression. Standard dilutions of eribulin in combination with log dilutions of RAD001 resulted in marked synergistic growth inhibition (CI<<1) in both MDA468 and BT549 cells. Western blot analysis for MDA468 cells treated with the combination erubulin and RAD001 showed a dose related suppression of pAkt along with complete inhibition of pS6K1, while RAD001 alone increased pAkt. Conclusions: Our study shows dose related inhibition of Akt activation as well as inhibition of cell growth in triple negative breast cancer and HER2 cell lines treated with eribulin alone or combined with RAD001. We also show reversal of the pAkt feedback response seen with mTOR inactivation, and a significant synergistic growth inhibition with combination treatment. These findings point to a potential role for eribulin and RAD001 in the treatment of refractory triple-negative breast cancer. [Table: see text]

scholarly journals BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells

2020 ◽  
Vol 15 (1) ◽  
pp. 501-510
Author(s):  
Bin Ma ◽  
Wenjia Guo ◽  
Meihui Shan ◽  
Nan Zhang ◽  
Binlin Ma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Nuclear Localization ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Pi3k Pathway ◽  
Pi3k Signaling ◽  
T47d Cells ◽  
Pi3k Signaling Pathway ◽  
Hormone Sensitive

AbstractThis study is to investigate the effect of the PI3K/Akt signaling pathway on the regulation of BRCA1 subcellular localization in triple-negative breast cancer (TNBC) MDA-MB-231 cells and hormone-sensitive T47D cells. We found that heregulin-activated T47D cells showed more nuclear localization of BRCA1, but BRCA1 nuclear localization decreased after the inhibition of the PI3K signaling pathway. In MDA-MB-231 cells, activation or inhibition of the PI3K signaling pathway did not significantly affect cell apoptosis and BRCA1 nuclear translocation (P > 0.05). However, in T47D cells, the activation of the PI3K pathway significantly increased cell apoptosis (P < 0.05). In the heregulin-activated MDA-MB-231 and T47D cells, the phosphorylation of Akt and BRCA1 was significantly increased (P < 0.05), while that was significantly reduced after PI3K pathway inhibition (P < 0.05). The changing trends of the mRNA levels of Akt and BRCA1 in MDA-MB-231 and T47D cells after PI3K pathway activation or inhibition were consistent with the trends of their proteins. In both MDA-MB-231 and T47D cells, BRCA1 phosphorylation is regulated by the PI3K signaling pathway, but the nuclear localization of BRCA1 is different in these two cell lines. Moreover, the apoptosis rates of these two cell lines are different.

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