Cell cycle control by steroid hormones in breast cancer: implications for endocrine resistance

1995 ◽  
Vol 2 (1) ◽  
pp. 87-96 ◽  
Author(s):  
R L Sutherland ◽  
C K W Watts ◽  
E A Musgrove
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Steroid Hormones ◽  
Cell Cycle Control ◽  
Endocrine Resistance

scholarly journals Killing the second messenger: targeting loss of cell cycle control in endocrine-resistant breast cancer

2011 ◽  
Vol 18 (4) ◽  
pp. C19-C24 ◽  
Author(s):  
Carol A Lange ◽  
Douglas Yee
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Control ◽  
Endocrine Resistance ◽  
Cell Cycle Checkpoint ◽  
Regulatory Subunit ◽  
Breast Cancers ◽  
Checkpoint Control ◽  
Estrogen Synthesis

The majority (∼70%) of breast cancers are steroid hormone receptor (SR) positive at the time of diagnosis. Endocrine therapies that target estrogen receptor α (ERα) action (tamoxifen, toremifene, fulvestrant) or estrogen synthesis (aromatase inhibitors: letrozole, anastrozole, exemestane; or ovarian suppression) are a clinical mainstay. However, up to 50% of SR+ breast cancers exhibit de novo or acquired resistance to these clinical interventions. Mechanisms of resistance to endocrine therapies often include upregulation and/or activation of signal transduction pathways that input to cell cycle regulation. Cyclin D1, the regulatory subunit of cyclin-dependent protein kinases four and six (CDK4/6) serves as a convergence point for multiple signaling pathways. In a recent paper entitled ‘Therapeutically Activating Retinoblastoma (RB): Reestablishing Cell Cycle Control in Endocrine Therapy-Resistant Breast Cancer’, Thangavel et al. reported maintenance of cyclin D1 expression and RB phosphorylation in the face of ER ablation in multiple breast cancer cell line models of endocrine resistance. RB-dysfunction defined a unique gene signature that was associated with luminal B-type breast cancer and predictive of poor response to endocrine therapies. Notably, a new CDK4/6 inhibitor (PD-0332991) was capable of inducing growth arrest by a mechanism that was most consistent with cellular senescence. In this review, these findings are discussed in the context of SRs as important mediators of cell cycle progression, and the frequent loss of cell cycle checkpoint control that typifies breast cancer progression. These studies provide renewed hope of effectively stabilizing endocrine-resistant breast cancers using available complementary (to endocrine-based therapies) cytostatic agents in the form of CDK4/6 inhibitors.

scholarly journals Progress with palbociclib in breast cancer: latest evidence and clinical considerations

2016 ◽  
Vol 9 (2) ◽  
pp. 83-105 ◽  
Author(s):  
Andrea Rocca ◽  
Alessio Schirone ◽  
Roberta Maltoni ◽  
Sara Bravaccini ◽  
Lorenzo Cecconetto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Randomized Clinical Trials ◽  
Cell Cycle Control ◽  
Endocrine Resistance ◽  
Cyclin D ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Cycle Progression

Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated. Among breast cancers, those with functioning cyclin D-CDK4/6-Rb-E2F are mainly hormone-receptor (HR) positive, with some HER2-positive and rare triple-negative cases. Deregulation results from genetic or otherwise occurring hyperactivation of molecules subtending cell cycle progression, or inactivation of cell cycle inhibitors. Based on results of randomized clinical trials, palbociclib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with HR-positive, HER2-negative breast cancer, and was approved for use in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. This review provides an update of the available knowledge on the cell cycle and its regulation, on the alterations in cyclin D-CDK4/6-Rb-E2F axis in breast cancer and their roles in endocrine resistance, on the preclinical activity of CDK4/6 inhibitors in breast cancer, both as monotherapy and as partners of combinatorial synergic treatments, and on the clinical development of palbociclib in breast cancer.

scholarly journals MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Sanne Løkkegaard ◽  
Daniel Elias ◽  
Carla L. Alves ◽  
Martin V. Bennetzen ◽  
Anne-Vibeke Lænkholm ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Endocrine Resistance ◽  
Predictive Marker ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Minichromosome Maintenance ◽  
Primary Tumors

AbstractResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in the cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser315,33), CHK1(Ser317), and cdc25b(Ser323), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Interestingly, the MCM3 levels did not affect the efficacy of growth inhibitory by CDK4/6 inhibitors. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic marker adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients.

scholarly journals Effects of common germline genetic variation in cell cycle control genes on breast cancer survival: results from a population-based cohort

2008 ◽  
Vol 10 (3) ◽  
Author(s):  
Elizabeth M Azzato ◽  
Kristy E Driver ◽  
Fabienne Lesueur ◽  
Mitul Shah ◽  
David Greenberg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Genetic Variation ◽  
Cancer Survival ◽  
Cell Cycle Control ◽  
Population Based ◽  
Breast Cancer Survival

scholarly journals A prognostic model based on cell-cycle control predicts outcome of breast cancer patients

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Heli Repo ◽  
Eliisa Löyttyniemi ◽  
Samu Kurki ◽  
Lila Kallio ◽  
Teijo Kuopio ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Patients ◽  
Prognostic Model ◽  
Cell Cycle Control ◽  
Breast Cancer Patients ◽  
Model Based

Abstract 233: Crosstalk of Her2 signaling and cell cycle control in the response to targeted therapeutics in breast cancer

2011 ◽  
Author(s):  
Dayana Rivadeneira ◽  
Isabelle Mercier ◽  
Michael P. Lisanti ◽  
Agnieska Witkiewicz ◽  
Erik S. Knudsen
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Cycle Control ◽  
Targeted Therapeutics ◽  
Her2 Signaling

scholarly journals Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

2020 ◽  
Vol 21 (18) ◽  
pp. 6479 ◽  
Author(s):  
Michela Piezzo ◽  
Stefania Cocco ◽  
Roberta Caputo ◽  
Daniela Cianniello ◽  
Germira Di Gioia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Clinical Outcomes ◽  
Cell Cycle Control ◽  
Acquired Resistance ◽  
Metastatic Breast ◽  
New Combination ◽  
Hormone Receptor Positive ◽  
Combination Strategies ◽  
New Biomarkers

Deregulation of cell cycle, via cyclin D/CDK/pRb pathway, is frequently observed in breast cancer lending support to the development of drugs targeting the cell cycle control machinery, like the inhibitors of the cycline-dependent kinases (CDK) 4 and 6. Up to now, three CDK4/6 inhibitors have been approved by FDA for the treatment of hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. These agents have been effective in improving the clinical outcomes, but the development of intrinsic or acquired resistance can limit the efficacy of these treatments. Clinical and translational research is now focused on investigation of the mechanism of sensitivity/resistance to CDK4/6 inhibition and novel therapeutic strategies aimed to improve clinical outcomes. This review summarizes the available knowledge regarding CDK4/6 inhibitor, the discovery of new biomarkers of response, and the biological rationale for new combination strategies of treatment.

Polymorphisms in XRCC1, XRCC3, and CCND1 and Survival After Treatment for Metastatic Breast Cancer

2006 ◽  
Vol 24 (36) ◽  
pp. 5645-5651 ◽  
Author(s):  
Mary A. Bewick ◽  
Michael S.C. Conlon ◽  
Robert M. Lafrenie
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Dna Repair ◽  
Metastatic Breast Cancer ◽  
Bone Metastases ◽  
Cell Cycle Control ◽  
Multivariable Analysis ◽  
Metastatic Breast ◽  
High Dose ◽  
Cancer Specific Survival

Purpose Single nucleotide polymorphisms (SNPs) in DNA repair and cell cycle control genes may alter protein function and therefore the efficacy of DNA damaging chemotherapy. We retrospectively evaluated the association of SNPs in DNA repair genes, XRCC1-01 (Arg399Gln) and XRCC3-01 (Thr241Met), and a cell cycle control gene, CCND1-02 (A870G), with progression-free survival (PFS) and breast cancer specific survival (BCSS) in patients with metastatic breast cancer (MBC). Patients and Methods SNPs in 95 patients with MBC enrolled onto one of five prospective clinical trials of high-dose chemotherapy and autologous stem-cell transplantation were evaluated using genotyping assays. Results For XRCC1-01, the hazard ratio (HR) for BCSS was 2.8 (95% CI, 1.60 to 5.00) and the HR for PFS was 2.0 (95%CI, 1.12 to 3.43). For XRCC3-01, the HR for BCSS was 2.0 (95%CI, 1.12 to 3.70) and the HR for PFS was 2.0 (95%CI, 1.09 to 3.59). For CCND1-02, the HR for BCSS was 1.8 (95%CI, 1.12 to 2.78) and the HR for PFS was 1.8 (95%CI, 1.15 to 2.85). Patients carrying one variant genotype (HR, 1.7; 95%CI, 1.07 to 2.82) or combinations of any two variant genotypes (HR, 4.7; 95% CI, 2.41 to 8.94) had significantly poorer BCSS compared with patients carrying zero variants. In multivariable analysis, XRCC1-01, presence of liver metastases, and bone metastases independently predicted BCSS. Combinations of any two variant genotypes were stronger independent predictors of BCSS and PFS than the presence of liver or bone metastases. Conclusion XRCC1-01, XRCC3-01, and CCND1-01 may be predictive of survival outcome in patients with MBC treated with DNA damaging chemotherapy.

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