QM-FISH analysis of the genes involved in the G1/S checkpoint signaling pathway in triple-negative breast cancer

Zhang, Sheng; Shao, Yuanhu; Hou, Guofang; Bai, Jingchao; Yuan, Weiping; Hu, Linping; Cheng, Tao; Zetterberg, Anders; Zhang, Jin

doi:10.1007/s13277-013-1246-5

Cited by 10 publications

(11 citation statements)

References 23 publications

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“…For instance, Rb inactivation, due to mutation or homozygous loss of the gene, is observed in around 7–20% of TNBC 7,8 . In addition, the loss of p16 INK4 occurs with high frequency in TNBC and has been correlated with the poor prognosis of this subtype 9 . An altered expression of cyclin D and E, CDK4/6, and CDK2 has also been observed in TNBC 10–12 .…”

Section: Introductionmentioning

confidence: 99%

Pre-treatment with the CDK4/6 inhibitor palbociclib improves the efficacy of paclitaxel in TNBC cells

Cretella

Fumarola

Bonelli

et al. 2019

Sci Rep

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Triple Negative Breast Cancer (TNBC) is a challenging disease due to the lack of druggable targets; therefore, chemotherapy remains the standard of care and the identification of new targets is a high clinical priority. Alterations in the components of the cell cycle machinery have been frequently reported in cancer; given the success obtained with the CDK4/6 inhibitor palbocicib in ER-positive BC, we explored the potential of combining this drug with chemotherapy in Rb-positive TNBC cell models. The simultaneous combination of palbociclib with paclitaxel exerted an antagonistic effect; by contrast, the sequential treatment inhibited cell proliferation and increased cell death more efficaciously than single treatments. By down-regulating the E2F target c-myc, palbociclib reduced HIF-1α and GLUT-1 expression, and hence glucose uptake and consumption both under normoxic and hypoxic conditions. Importantly, these inhibitory effects on glucose metabolism were enhanced by palbociclib/paclitaxel sequential combination; the superior efficacy of such combination was ascribed to the ability of paclitaxel to inhibit palbociclib-mediated induction of AKT and to further down-regulate the Rb/E2F/c-myc signaling. Our results suggest that the efficacy of standard chemotherapy can be significantly improved by a pre-treatment with palbociclib, thus offering a better therapeutic option for Rb-proficient TNBC.

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Section: Introductionmentioning

confidence: 99%

Pre-treatment with the CDK4/6 inhibitor palbociclib improves the efficacy of paclitaxel in TNBC cells

Cretella

Fumarola

Bonelli

et al. 2019

Sci Rep

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“…Loss of functional p16 INK4 gives rise to deregulated CDK4/6 activity, leading to persistent retinoblastoma protein (Rb) phosphorylation and increasing cell proliferation [ 4 ]. The loss of p16 INK4 has been reported to occur with higher frequency in TNBC in comparison with other BC histotypes and has been correlated with the poor prognosis of TNBC [ 5 ]. In addition, the lack of p16 INK4 expression has been associated with the acquisition of cancer stem cell-like properties and with a reduced response of TNBC to paclitaxel treatment [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

The anti-tumor efficacy of CDK4/6 inhibition is enhanced by the combination with PI3K/AKT/mTOR inhibitors through impairment of glucose metabolism in TNBC cells

Cretella

Ravelli

Fumarola

et al. 2018

J Exp Clin Cancer Res

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BackgroundCell cycle regulators have gain attention as potential targets for anticancer therapy. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which coordinate the G1-S transition. Palbociclib is currently approved for the treatment of hormone receptor positive, HER2-negative advanced breast cancer (BC) in association with letrozole or fulvestrant. In contrast, its efficacy in triple negative BC (TNBC), either alone or in combined therapies, has not been fully investigated to date.MethodsHere we evaluated the potential of combining palbociclib with PI3K/mTOR inhibitors in Rb-proficient TNBC cells comparing different schedules of treatment: simultaneous, sequential, or sequential combined treatment (pre-incubation with palbociclib followed by exposure to both palbociclib and PI3K/mTOR inhibitors). We assessed the effects on cell proliferation, cell death, and cell cycle distribution, and looked at the impact of such treatments on glucose metabolism.ResultsPalbociclib exerted cytostatic effects in Rb-positive TNBC cells, inducing a reversible blockade in G0/G1 cell cycle phase associated with down-regulation of CDK6, Rb, and c-myc expression and/or activity. Palbociclib treatment induced AKT signaling, providing a rationale for its combination with PI3K/mTOR inhibitors. The simultaneous or sequential treatment resulted in an additive inhibition of cell proliferation. On the other hand, the sequential combined treatment in which palbociclib was maintained also during exposure to PI3K/mTOR inhibitors gave rise to synergistic anti-proliferative and pro-apoptotic effects, by inhibiting both CDK4/6/Rb/myc and PI3K/mTOR signaling. Interestingly, the inhibition of the Rb/E2F/myc axis mediated by palbociclib resulted in a significant down-regulation of glucose metabolism; most importantly, these inhibitory effects were enhanced by the combination of palbociclib with BYL719 (specific inhibitor of the p110α PI3K-subunit), which promoted a stronger inhibition of GLUT-1 glucose transporter expression, glucose uptake and consumption in comparison with individual treatments, under both normoxic and hypoxic conditions.ConclusionsCombination of palbociclib with PI3K/mTOR inhibitors may represent a promising therapeutic option for the treatment of Rb-proficient TNBC, with the sequential combined schedule showing a superior efficacy over the other schedules. In addition our results demonstrate that the impairment of glucose metabolism may contribute to the anti-tumor activity of such drug combinations.

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“…The ovarian cancer cell sections were prepared by Cytospin procedure and fixed overnight in methanol. qmFISH was performed as previously described [ 93 ]. In each case, at least 200 nuclei were scored for CNAs (copy number alterations) of c-myc, Rb1, Chk2, p53 and BRCA1.…”

Section: Introductionmentioning

confidence: 99%

Fluorescence in situ hybridization (FISH): an increasingly demanded tool for biomarker research and personalized medicine

Zhang

et al. 2014

Biomark Res

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Extensive studies of the genetic aberrations related to human diseases conducted over the last two decades have identified recurrent genomic abnormalities as potential driving factors underlying a variety of cancers. Over the time, a series of cutting-edge high-throughput genetic tests, such as microarrays and next-generation sequencing, have been developed and incorporated into routine clinical practice. Although it is a classical low-throughput cytogenetic test, fluorescence in situ hybridization (FISH) does not show signs of fading; on the contrary, it plays an increasingly important role in detecting specific biomarkers in solid and hematologic neoplasms and has therefore become an indispensable part of the rapidly developing field of personalized medicine. In this article, we have summarized the recent advances in FISH application for both de novo discovery and routine detection of chromosomal rearrangements, amplifications, and deletions that are associated with the pathogenesis of various hematopoietic and non-hematopoietic malignancies. In addition, we have reviewed the recent developments in FISH methodology as well.

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QM-FISH analysis of the genes involved in the G1/S checkpoint signaling pathway in triple-negative breast cancer

Cited by 10 publications

References 23 publications

Pre-treatment with the CDK4/6 inhibitor palbociclib improves the efficacy of paclitaxel in TNBC cells

Pre-treatment with the CDK4/6 inhibitor palbociclib improves the efficacy of paclitaxel in TNBC cells

The anti-tumor efficacy of CDK4/6 inhibition is enhanced by the combination with PI3K/AKT/mTOR inhibitors through impairment of glucose metabolism in TNBC cells

Fluorescence in situ hybridization (FISH): an increasingly demanded tool for biomarker research and personalized medicine

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