• RB pathway
• Triple-negative breast cancer
• p16 immunohistochemistry
• pRB-deficient tumor

• Humans
• Triple Negative Breast Neoplasms/genetics
• Triple Negative Breast Neoplasms/pathology
• Triple Negative Breast Neoplasms/metabolism
• Female
• Cyclin-Dependent Kinase Inhibitor p16/genetics
• Cyclin-Dependent Kinase Inhibitor p16/metabolism
• Immunohistochemistry
• Middle Aged
• Retinoblastoma Protein/genetics
• Retinoblastoma Protein/deficiency
• Adult
• Retinoblastoma Binding Proteins/genetics
• Aged
• Mutation
• Exome Sequencing
• Ubiquitin-Protein Ligases

• Humans
• Retinoblastoma/genetics
• Codon, Nonsense/genetics
• Retinoblastoma Protein/genetics
• Protein Biosynthesis
• Retinal Neoplasms/pathology
• Ubiquitin-Protein Ligases/genetics
• Retinoblastoma Binding Proteins/genetics

• European Research Council
• Barncancerfonden
• Vetenskapsrådet
• Cancerfonden
• Karolinska Institutet

• ERα nucleo-cytoplasmic transport
• ERα stability
• breast cancer
• endocrine resistance
• estrogen receptor alpha
• therapeutic approaches

• Estrogen Receptor alpha
• Estrogens
• Neoplasms
• Transcription Factors

• CTCs
• breast cancer
• gene expression
• metastasis
• molecular/gene signature
• predictive biomarkers

• Apoptosis
• CDK4/6 inhibitors
• Cancer therapy
• Immunotherapy
• Predictive role
• RB1

• Estrogen receptor alpha
• breast cancer
• endocrine therapy
• monoubiquitination
• non-covalent ubiquitin binding
• polyubiquitination.

• Breast cancer
• Estrogen receptor alpha
• Estrogen receptor alpha polyubiquitination

• CDK4/6 inhibitor
• abemaciclib
• breast cancer
• hormone receptor-positive BC
• mBC
• metastatic BC

• Aminopyridines/adverse effects
• Aminopyridines/therapeutic use
• Animals
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Benzimidazoles/adverse effects
• Benzimidazoles/therapeutic use
• Breast Neoplasms/drug therapy
• Breast Neoplasms/enzymology
• Breast Neoplasms/pathology
• Cyclin-Dependent Kinase 4/antagonists & inhibitors
• Cyclin-Dependent Kinase 4/metabolism
• Cyclin-Dependent Kinase 6/antagonists & inhibitors
• Cyclin-Dependent Kinase 6/metabolism
• Female
• Hormone Antagonists/therapeutic use
• Humans
• Protein Kinase Inhibitors/adverse effects
• Protein Kinase Inhibitors/therapeutic use
• Receptor, ErbB-2/deficiency
• Receptors, Estrogen/metabolism
• Receptors, Progesterone/metabolism
• Signal Transduction/drug effects
• Treatment Outcome

Hallmarks of cancer cells include uncontrolled growth and rapid proliferation; thus, cyclin-dependent kinases are a therapeutic target for cancer treatment. Treating non-small lung cancer cells with sublethal concentrations of the CDK4/6 inhibitors, ribociclib (LEE011) and palbociclib (PD0332991), which are approved by the FDA for anticancer therapies, caused cell cycle arrest in the G1 phase and suppression of poly(ADP-ribose) polymerase 1 (PARP1) transcription by inducing recruitment of the RB1-E2F1-HDAC1-EZH2 repressive complex to the PARP1 promoter. Downregulation of PARP1 made cancer cells vulnerable to death triggered by the anticancer drugs (WP631 and etoposide) and H₂O₂. All agents brought about redox imbalance and DNA strand breaks. The lack of PARP1 and poly(ADP-ribosyl)ation impaired the 8-oxoguanine glycosylase (OGG1)-dependent base excision DNA repair pathway, which is critical for maintaining the viability of cells treated with CDK4/6 inhibitors during oxidative stress. Upon G1 arrest of PARP1 overexpressing cells, OGG1 formed an immunoprecipitable complex with PARP1. Similar to cells with downregulated PARP1 expression, inhibition of PARP1 or OGG1 in PARP1 overexpressing cells resulted in DNA damage and decreased viability. Thus, PARP1 and OGG1 act in the same regulatory pathway, and PARP1 activity is required for OGG1-mediated repair of oxidative DNA damage in G1-arrested cells. In conclusion, the action of CDK4/6 inhibitors is not limited to the inhibition of cell growth. CDK4/6 inhibitors also lead to accumulation of DNA damage by repressing PARP1 in oxidatively stressed cells. Thus, CDK4/6 inhibitors sensitize G1-arrested cells to anticancer drugs, since these cells require PARP1-OGG1 functional interaction for cell survival.

•

CDK4/6 inhibitors arrest cell proliferation in G1 phase.

• 8-oxoguanine glycosylase (OGG1)
• Cyclin-dependent kinase 4 and 6 (iCDK4/6)
• Poly(ADP-ribose) polymerase 1 (PARP1)
• Reactive oxygen species (ROS)

The design of novel pharmacologic agents as well as their approval for sale in markets all over the world is a tedious and pricey process. Inevitably, oncologic patients commonly experience unwanted effects of new anticancer drugs, while the acquisition of clinical experience for these drugs is largely based on doctor–patient partnership which is not always effective. The repositioning of marketed non-antineoplastic drugs that hopefully exhibit anticancer properties into the field of oncology is a challenging option that gains ground and attracts preclinical and clinical research in an effort to override all these hindrances and minimize the risk for reduced efficacy and/or personalized toxicity. This review aims to present the anticancer properties of drugs used for the management of hypercholesterolemia. A global view of the antitumorigenicity of all marketed antihypercholesterolemic drugs is of major importance, given that atherosclerosis, which is etiologically linked to hypercholesterolemia, is a leading worldwide cause of morbidity and mortality, while hypercholesterolemia and tumorigenesis are known to be interrelated. In vitro, in vivo and clinical literature data accumulated so far outline the mechanistic basis of the antitumor function of these agents and how they could find application at the clinical setting.

• antihypercholesterolemic agents
• cancer
• repurposing
• synergism

• BC
• Cancer
• Metastatic BC
• Systemic

• Antineoplastic Agents/pharmacology
• Breast Neoplasms/genetics
• Breast Neoplasms/pathology
• Breast Neoplasms/therapy
• Estrogen Receptor alpha/genetics
• Female
• High-Throughput Nucleotide Sequencing
• Humans
• Immunotherapy/methods
• Molecular Targeted Therapy/methods
• Mutation
• Receptor, ErbB-2/metabolism
• Receptors, Progesterone/metabolism
• Triple Negative Breast Neoplasms/pathology
• Triple Negative Breast Neoplasms/therapy

Loss or dysfunction of tumor suppressor retinoblastoma (RB) is a common feature in various tumors, and contributes to cancer cell stemness and drug resistance to cancer therapy. However, the strategy to suppress or eliminate Rb-deficient tumor cells remains unclear. In the present study, we accidentally found that reduction of DNA replication licensing factor MCM7 induced more apoptosis in RB-deficient tumor cells than in control tumor cells. Moreover, after a drug screening and further studies, we demonstrated that statin drug Simvastatin and Atorvastatin were able to inhibit MCM7 and RB expressions. Further study showed that Simvastatin and Atorvastatin induced more chromosome breaks and gaps of Rb-deficient tumor cells than control tumor cells. In vivo results showed that Simvastatin and Atorvastatin significantly suppressed Rb-deficient tumor growth than control in xenograft mouse models. The present work demonstrates that ‘old' lipid-lowering drugs statins are novel weapons against RB-deficient tumors due to their effects on suppressing MCM7 protein levels.

• Abemaciclib
• Advanced breast cancer
• Breast cancer
• Cyclin-dependent kinases (CDK)
• HER2 positive BC
• Palbociclib
• Ribociclib

Acquired tamoxifen resistance (TamR) remains a major challenge in breast cancer endocrine therapy. The mechanism of acquiring tamoxifen resistance remains elusive, and no effective drugs are available. In this investigation, we determined that the expression of the DNA damage marker γH2AX is upregulated under minichromosome maintenance protein 7 (MCM7) knockdown in phospho Ser807/811-retinoblastoma protein (p-Rb) defect cells. In addition, the expression of p-Rb was lower in TamR cells than in parental cells, and the expression of γH2AX was significantly upregulated when MCM7 was knocked down in TamR cells. Simvastatin, an agent for hypercholesterolemia treatment, activated the MCM7/p-RB/γH2AX axis and induced DNA damage in TamR cells, especially when combined with tamoxifen. Finally, in vitro and in vivo experiments demonstrated that simvastatin combined with tamoxifen increased TamR cell apoptosis and inhibited xenograft growth. In conclusion, simvastatin may suppress TamR cell growth by inhibiting MCM7 and Rb and subsequently inducing DNA damage.

• ER
• ER degradation
• ER protein stability
• ER upregulation
• Estrogen signaling pathway

• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Estrogen Receptor alpha/chemistry
• Estrogen Receptor alpha/metabolism
• Female
• Humans
• Protein Stability

• CDK inhibitors
• E2F
• RB family
• apoptosis
• cancer therapy

Acquired or de novo resistance to the selective estrogen receptor modulators tamoxifen and fulvestrant (ICI) is a major barrier to successful treatment of breast cancer. Gene expression patterns in tamoxifen resistant (TamR-MCF-7) cells were compared to their parental cells (MCF-7L) to identify an aberrantly regulated metabolic pathway. TamR-MCF-7 cells are cross resistant to ICI and doxorubicin, and have increased mitochondrial DNA. A small subset of genes had altered expression in TamR-MCF-7 relative to MCF-7L cells. One of the genes, pyruvate dehydrogenase kinase-4 (PDK4), phosphorylates pyruvate dehydrogenase (PDH). PDK4 expression was elevated in TamR-MCF-7 cells; this result was also observed in a second model of acquired antiestrogen resistance. PDK4 expression is controlled in part by glucocorticoid response elements in the PDK4 gene promoter. In MCF-7L cells, PDK4 mRNA expression was insensitive to glucocorticoid receptor agonists, while dexamethasone dramatically increased PDK4 expression in TamR-MCF-7 cells. Using siRNA to knock down PDK4 expression increased TamR-MCF-7 sensitivity to ICI; in contrast adapting cells to growth in glucose depleted media did not affect ICI sensitivity. Despite TamR-MCF-7 cells high levels of PDK4 mRNA relative to MCF-7L, TamR-MCF-7 cells have increased PDH activity. Wild type MCF-7 cells are reported to be heterozygous for a G to A mutation that results in a substitution of threonine for alanine near PDK4′s catalytic site. We found loss of heterozygosity in TamR-MCF-7 cells; TamR-MCF-7 are homozygous for the wild type allele. These data support a role for altered regulation of PDH by PDK4 and altered substrate utilization in the development of drug resistance in human breast cancer cells.

• Antiestrogen resistance
• Breast cancer
• Glucose
• Metabolism
• Pyruvate dehydrogenase kinase-isoform 4 (PDK4)

• Cancer stem cells
• ER
• HER2
• Hormonal therapy
• Targeted therapy
• Therapy resistance
• miRs

• Antineoplastic Agents/pharmacology
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Female
• Humans
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Proteins/genetics
• Proteins/metabolism

Cellular proliferation, growth, and division following DNA (deoxyribonucleic acid) damage are tightly controlled by the cell-cycle regulatory machinery. This machinery includes cyclin-dependent kinases (CDKs) which complex with their cyclin partners, allowing the cell cycle to progress. The cell-cycle regulatory process plays a critical role in oncogenesis and in the development of therapeutic resistance; it is frequently disrupted in breast cancer, providing a rational target for therapeutic development. Palbociclib is a potent and selective inhibitor of CDK4 and -6 with significant activity in breast cancer models. Furthermore, it has been shown to significantly prolong progression-free survival when combined with letrozole in the management of estrogen receptor-positive metastatic breast cancer. In this article we review the cell cycle and its regulatory processes, their role in breast cancer, and the rationale for CDK inhibition in this disease. We describe the preclinical and clinical data relating to the activity of palbociclib in breast cancer and the plans for the future development of this agent.

• CDK4/6 inhibition
• cell-cycle regulation
• cyclin-dependent kinases

• ER+ breast cancer
• ERK/MAPK
• estrogen-related receptor γ
• tamoxifen
• transcription

• Antineoplastic Agents, Hormonal/pharmacology
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Drug Resistance, Neoplasm/genetics
• Drug Resistance, Neoplasm/physiology
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• MAP Kinase Signaling System
• MCF-7 Cells
• Mutagenesis, Site-Directed
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• RNA, Neoplasm/genetics
• RNA, Neoplasm/metabolism
• Receptors, Estrogen/chemistry
• Receptors, Estrogen/genetics
• Receptors, Estrogen/metabolism
• Recombinant Proteins/chemistry
• Recombinant Proteins/genetics
• Recombinant Proteins/metabolism
• Selective Estrogen Receptor Modulators/pharmacology
• Tamoxifen/pharmacology

• HHSN2612200800001E PHS HHS
• T32-CA-009686 NCI NIH HHS
• HHSN261200800001C NCI NIH HHS
• P30 CA051008 NCI NIH HHS
• P30-CA-51008 NCI NIH HHS
• T32 CA009686 NCI NIH HHS
• HHSN261200800001E NCI NIH HHS
• U54-CA-149147 NCI NIH HHS
• U54 CA149147 NCI NIH HHS

• GSK-3β
• MEK
• PI3K
• mTOR
• rapamycin
• sorafenib
• targeted therapy
• therapy resistance
• β-catenin

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Targeting these pathways is often complex and can result in pathway activation depending on the presence of upstream mutations (e.g., Raf inhibitors induce Raf activation in cells with wild type (WT) RAF in the presence of mutant, activated RAS) and rapamycin can induce Akt activation. Targeting with inhibitors directed at two constituents of the same pathway or two different signaling pathways may be a more effective approach. This review will first evaluate potential uses of Raf, MEK, PI3K, Akt and mTOR inhibitors that have been investigated in pre-clinical and clinical investigations and then discuss how cancers can become insensitive to various inhibitors and potential strategies to overcome this resistance.

• ngal
• lcn2
• lipocalins
• siderocalins
• targeted therapy
• inhibitor sensitivity
• egfr
• rapamycin
• berberine
• bcl-2
• calmodulin kinase
• breast cancer
• colorectal cancer

• Acute-Phase Proteins/genetics
• Acute-Phase Proteins/metabolism
• Antibiotics, Antineoplastic/pharmacology
• Benzylamines/pharmacology
• Berberine/pharmacology
• Biphenyl Compounds/pharmacology
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors
• Calcium-Calmodulin-Dependent Protein Kinases/metabolism
• Cell Line, Tumor
• Doxorubicin/pharmacology
• Drug Resistance, Neoplasm/drug effects
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/metabolism
• Female
• Gene Expression/drug effects
• HT29 Cells
• Humans
• Lipocalin-2
• Lipocalins/genetics
• Lipocalins/metabolism
• MCF-7 Cells
• Nitrophenols/pharmacology
• Piperazines/pharmacology
• Protein Kinase Inhibitors/pharmacology
• Proto-Oncogene Proteins/genetics
• Proto-Oncogene Proteins/metabolism
• Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Quinazolines/pharmacology
• Sirolimus/pharmacology
• Sulfonamides/pharmacology
• Tyrphostins/pharmacology

Signal transducer and activator of transcripton-5a (Stat5a) and its close homologue, Stat5b, mediate key physiological effects of prolactin and growth hormone in mammary glands. In breast cancer, loss of nuclear localized and tyrosine phosphorylated Stat5a/b is associated with poor prognosis and increased risk of antiestrogen therapy failure. Here we quantify for the first time levels of Stat5a and Stat5b over breast cancer progression, and explore their potential association with clinical outcome.

Stat5a and Stat5b protein levels were quantified in situ in breast-cancer progression material. Stat5a and Stat5b transcript levels in breast cancer were correlated with clinical outcome in 936 patients. Stat5a protein was further quantified in four archival cohorts totaling 686 patients with clinical outcome data by using multivariate models.

Protein levels of Stat5a but not Stat5b were reduced in primary breast cancer and lymph node metastases compared with normal epithelia. Low tumor levels of Stat5a but not Stat5b mRNA were associated with poor prognosis. Experimentally, only limited overlap between Stat5a- and Stat5b-modulated genes was found. In two cohorts of therapy-naïve, node-negative breast cancer patients, low nuclear Stat5a protein levels were an independent marker of poor prognosis. Multivariate analysis of two cohorts treated with antiestrogen monotherapy revealed that low nuclear Stat5a levels were associated with a more than fourfold risk of unfavorable outcome.

Loss of Stat5a represents a new independent marker of poor prognosis in node-negative breast cancer and may be a predictor of response to antiestrogen therapy if validated in randomized clinical trials.

• Aromatase Inhibitors/therapeutic use
• Breast Neoplasms/drug therapy
• Breast Neoplasms/metabolism
• Cell Cycle
• Female
• Humans
• Neoplasms, Hormone-Dependent/drug therapy
• Neoplasms, Hormone-Dependent/metabolism
• Retinoblastoma Protein/metabolism
• Second Messenger Systems/drug effects

• R01 DK53825 NIDDK NIH HHS
• R01CA 74285 NCI NIH HHS
• R01 DK053825 NIDDK NIH HHS
• P30 CA 077598 NCI NIH HHS
• R01 CA074285 NCI NIH HHS
• R01 CA123763 NCI NIH HHS
• P30 CA077598 NCI NIH HHS