Defining the Prognostic and Predictive Role of PIK3CA Mutations: Sifting Through the Conflicting Data

Al-Sukhun, Sana; Lataifeh, Isam; Al-Sukhun, Rajaa

doi:10.1007/s12609-016-0215-6

Cited by 7 publications

(4 citation statements)

References 64 publications

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“…Furthermore, PIK3CA mutations are key drivers of breast cancer and its upregulation is associated with poor prognosis (50). Noteworthy, PIK3CA mutations are more frequent in estrogen receptor cancer cells, such as like MCF7 (51). In this study we demonstrate that lactate exposure to MCF7 cells is able to increase the transcriptional activity of PIK3CA between 2.2-and 4.3-fold (p < 0.05-0.001) ( Table 1, Figures 2, 3A,B).…”

Section: Discussionmentioning

confidence: 99%

Is Lactate an Oncometabolite? Evidence Supporting a Role for Lactate in the Regulation of Transcriptional Activity of Cancer-Related Genes in MCF7 Breast Cancer Cells

et al. 2020

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Lactate is a ubiquitous molecule in cancer. In this exploratory study, our aim was to test the hypothesis that lactate could function as an oncometabolite by evaluating whether lactate exposure modifies the expression of oncogenes, or genes encoding transcription factors, cell division, and cell proliferation in MCF7 cells, a human breast cancer cell line. Gene transcription was compared between MCF7 cells incubated in (a) glucose/glutamine-free media (control), (b) glucose-containing media to stimulate endogenous lactate production (replicating some of the original Warburg studies), and (c) glucose-containing media supplemented with L-lactate (10 and 20 mM). We found that both endogenous, glucose-derived lactate and exogenous, lactate supplementation significantly affected the transcription of key oncogenes (MYC, RAS, and PI3KCA), transcription factors (HIF1A and E2F1), tumor suppressors (BRCA1, BRCA2) as well as cell cycle and proliferation genes involved in breast cancer (AKT1, ATM, CCND1, CDK4, CDKN1A, CDK2B) (0.001 < p < 0.05 for all genes). Our findings support the hypothesis that lactate acts as an oncometabolite in MCF7 cells. Further research is necessary on other cell lines and biopsy cultures to show generality of the findings and reveal the mechanisms by which dysregulated lactate metabolism could act as an oncometabolite in carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Is Lactate an Oncometabolite? Evidence Supporting a Role for Lactate in the Regulation of Transcriptional Activity of Cancer-Related Genes in MCF7 Breast Cancer Cells

et al. 2020

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“…61,[124][125][126] Of the 3, the only currently FDA approved is alpelisib in combination with fulvestrant for postmenopausal women or men, who have HR+, HER2−, PIK3CA mutated, ABC or MBC (Figure 1). [127][128][129][130][131][132] Alpelisib works as an α-specific PI3K inhibitor, by selectively inhibiting p110α, leading to interruption of PI3K signaling pathways. [128][129][130][131][132] The SOLAR-1 trial alpelisib + fulvestrant resulted in a PFS of 11 months versus 5.7 months in the placebo group.…”

Section: Hormone-based Therapiesmentioning

confidence: 99%

“…[127][128][129][130][131][132] Alpelisib works as an α-specific PI3K inhibitor, by selectively inhibiting p110α, leading to interruption of PI3K signaling pathways. [128][129][130][131][132] The SOLAR-1 trial alpelisib + fulvestrant resulted in a PFS of 11 months versus 5.7 months in the placebo group. This effect was only seen in patients with PIK3CA mutated cancer, though, with the effect disappearing in those without the mutation.…”

Section: Hormone-based Therapiesmentioning

confidence: 99%

Breast Cancer Therapeutics and Biomarkers: Past, Present, and Future Approaches

Schick

Ritchie

Restini

2021

Breast Cancer�(Auckl)

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Breast cancer (BC) is the leading cause of cancer death in women and the second-most common cancer. An estimated 281 550 new cases of invasive BC will be diagnosed in women in the United States, and about 43 600 will die during 2021. Continual research has shed light on all disease areas, including tumor classification and biomarkers for diagnosis/prognosis. As research investigations evolve, new classes of drugs are emerging with potential benefits in BC treatment that are covered in this manuscript. The initial sections present updated classification and terminology used for diagnosis and prognosis, which leads to the following topics, discussing the past and present treatments available for BC. Our review will generate interest in exploring the complexity of the cell cycle and its association with cancer biology as part of the plethora of target factors toward developing newer drugs and effective therapeutic management of BC.

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“…In the past decades, the antihormonal and anti-Her2 targeted therapies on specific BC subsets contributed to the significantly improved long-term survival (4). Recently developed targeted therapy agents, such as anti-PI3KCA mutant inhibitors and anti-CDK4/6 inhibitors, also demonstrate clinical benefits (5,6).…”

Section: Introductionmentioning

confidence: 99%

FOXK2amplification and overexpression promotes breast cancer development and chemoresistance

Cao

Cheng

et al. 2023

Preprint

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Activation of oncogenes through DNA amplification/overexpression plays an important role in cancer initiation and progression. Chromosome 17 has many cancer-associated genetic anomalies. This cytogenetic anomaly is strongly associated with poor prognosis of breast cancer.FOXK2gene is located on 17q25 and encodes a transcriptional factor with a forkhead DNA binding domain. By integrative analysis of public genomic datasets of breast cancers, we found thatFOXK2is frequently amplified and overexpressed in breast cancers. FOXK2 overexpression in breast cancer patients is associated with poor overall survival.FOXK2knockdown significantly inhibits cell proliferation, invasion and metastasis, and anchorage-independent growth, as well as causes G0/G1 cell cycle arrest in breast cancer cells. Moreover, inhibition of FOXK2 expression sensitizes breast cancer cells to frontline anti-tumor chemotherapies. More importantly, co-overexpression of FOXK2 and PI3KCA with oncogenic mutations (E545K or H1047R) induces cellular transformation in non-tumorigenic MCF10A cells, suggesting thatFOXK2is an oncogene in breast cancer and is involved in PI3KCA-driven tumorigenesis. Our study identifiedCCNE2,PDK1, and Estrogen receptor alpha (ESR1) as direct transcriptional targets of FOXK2 in MCF-7 cells. Blocking CCNE2- and PDK1-mediated signaling by using small molecule inhibitors has synergistic anti-tumor effects in breast cancer cells. Furthermore, FOXK2 inhibition by gene knockdown or inhibitors for its transcriptional targets (CCNE2 and PDK1) in combination with PI3KCA inhibitor, Alpelisib, showed synergistic anti-tumor effects on breast cancer cells with PI3KCA oncogenic mutations. In summary, we provide compelling evidence that FOXK2 plays an oncogenic role in breast tumorigenesis and targeting FOXK2-mediated pathways may be a potential therapeutic strategy in breast cancer.

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Defining the Prognostic and Predictive Role of PIK3CA Mutations: Sifting Through the Conflicting Data

Cited by 7 publications

References 64 publications

Is Lactate an Oncometabolite? Evidence Supporting a Role for Lactate in the Regulation of Transcriptional Activity of Cancer-Related Genes in MCF7 Breast Cancer Cells

Is Lactate an Oncometabolite? Evidence Supporting a Role for Lactate in the Regulation of Transcriptional Activity of Cancer-Related Genes in MCF7 Breast Cancer Cells

Breast Cancer Therapeutics and Biomarkers: Past, Present, and Future Approaches

FOXK2amplification and overexpression promotes breast cancer development and chemoresistance

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