Modulated Expression of Genes Encoding Estrogen Metabolizing Enzymes by G1-Phase Cyclin-Dependent Kinases 6 and 4 in Human Breast Cancer Cells

Jia, Yi; Domenico, Joanne; Swasey, Christina H.; Wang, Meiqin; Gelfand, Erwin W.; Lucas, Joseph J.

doi:10.1371/journal.pone.0097448

Cited by 6 publications

(4 citation statements)

References 48 publications

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“…In theory, overexpression of cyclin D1 can induce the hyperactivation of CDK4 and CDK6 40. The expression of CDK4 is essential for the development of breast cancer, while the level of CDK6 is decreased in many breast tumors and in most breast tumor-derived cell lines 41, 42. Yu Q et al demonstrated that re-expression of human wild-type CDK4 endowed the cells with the ability to form tumors 7.…”

Section: The Role Of Cdk4/6 Inhibitors In Breast Cancermentioning

confidence: 99%

Cyclin-Dependent Kinases 4/6 Inhibitors in Breast Cancer: Current Status, Resistance, and Combination Strategies

Niu¹,

Xu²,

Sun³

2019

J. Cancer

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Dysregulated activation of the cyclin-dependent kinases (CDKs) 4/6, leading to uncontrolled cell division, is hallmark of cancers. Further study of the cell cycle will advance the cancer treatment. As powerful and effective drugs, inhibitors of CDK 4/6 have been widely used in clinical practice for several malignancies, particularly against breast cancers driven by the estrogen receptor (ER). Three CDK4/6 inhibitors, including palbociclib (PD0332991), ribociclib (LEE011) and abemaciclib (LY2835219), have been approved by the US Food and Drug Administration (FDA) for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer. However, CDK4/6 inhibitors act downstream of many mitogenic signaling pathways, and this has implications for resistance. It is worth to note that the mechanisms of resistance are not very clear. Up to now, a small number of preclinical and clinical studies have explored potential mechanisms of CDK4/6 inhibitors resistance in breast cancer. On this basis, rational and effective combination therapy is under development. Here we review the current knowledge about the mechanisms and efficacy of CDK4/6 inhibitors, and summarize data on resistance mechanisms to make future combination therapies more accurate and reasonable.

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Section: The Role Of Cdk4/6 Inhibitors In Breast Cancermentioning

confidence: 99%

Cyclin-Dependent Kinases 4/6 Inhibitors in Breast Cancer: Current Status, Resistance, and Combination Strategies

Niu¹,

Xu²,

Sun³

2019

J. Cancer

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“…Among them, 21 genes are related to breast cancer/cancer/CYP and have been reported to promote cell migration and proliferation, and cancer metastasis. The upregulated genes that correlate positively with the malignancy of ER-positive breast cancer are UGT2B15 [ 16 ], AKR1C3 [ 17 ], ALCAM [ 8 ], and PTPRN2 [ 18 ]; the downregulated genes are JAK2 , STAT1 [ 19 ], CCNA1 [ 20 ]. Of note, UGT2B15 and AKR1C3 are genes related to the CYP pathway, and ALCAM and PTPRN2 are genes co-expressed with CCNA1 (Online Resource 5).…”

Section: Resultsmentioning

confidence: 99%

“…6 together with the previously reported genes [ 27 – 30 ]. Among the upregulated genes, UGT2B15 and AKR1C3 are included in the CYP metabolic pathway as per KEGG pathway analyses, suggesting the association between the CYP and Wnt5a pathways in the context of drug sensitivity [ 16 , 17 ]. Interestingly, ALCAM and PTPRN2 were also shown to correlate with Wnt5a expression and to promote cell migration [ 8 , 18 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of Wnt5a on drug resistance in estrogen receptor-positive breast cancer

et al. 2021

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Background Previously, we reported that Wnt5a-positive breast cancer can be classified as estrogen receptor (ER)-positive breast cancer; its prognosis is worse than that of Wnt5a-negative breast cancer. This study aimed to investigate the mechanisms underlying the poor prognosis in Wnt5a-positive breast cancer patients. Methods In total, 151 consecutive ER-positive breast cancer patients who underwent resection between January 2011 and February 2014 were enrolled. DNA microarray and pathway analyses were conducted using MCF-7 cells stably expressing Wnt5a [MCF-7/Wnt5a (+)]. Based on the outcomes, cell viability/drug sensitivity assays, and mutation analysis were performed using cell cultures and breast cancer tissues. The relationship between Wnt5a and the PI3K–AKT–mTOR signaling pathway was also examined. Results The relapse-free survival rate in patients with Wnt5a-positive breast cancer was significantly lower than that in patients with Wnt5a-negative breast cancer (P = 0.047). DNA microarray data suggest that only the cytochrome P450 (CYP) pathway was significantly upregulated in MCF-7/Wnt5a (+) cells (P = 0.0440). Additionally, MCF-7/Wnt5a (+) cells displayed reduced sensitivity to the metabolic substrates of CYP, tamoxifen (P < 0.001), paclitaxel (P < 0.001), and cyclophosphamide (P < 0.001). Of note, PIK3CA mutations were not associated with the expression of Wnt5a in breast cancer tissue and culture cells. Conclusions In ER-positive breast cancer, Wnt5a upregulates the CYP metabolic pathway and suppresses tamoxifen, paclitaxel, and cyclophosphamide resistance, all of the three, standard treatment methods for ER-positive breast cancer. Wnt5a is thus potentially involved in the poor prognosis of ER-positive breast cancer independently of the PI3K–AKT–mTOR signaling pathway.

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“…Given that ER activation, among other stimuli, can induce c-myc and CCND1 expression (5), CDK4 and CDK6 represent a nexus of signaling between the ER pathway and growth-promoting pathways in the cell. More recent data suggest that CDK4 and CDK6 can also regulate levels of steroid-metabolizing enzymes, including the AKR1C family, influencing the estrogenic state of breast tumors (6).…”

mentioning

confidence: 99%

“Braking” the Cycle of Resistance in Endocrine Therapy for Breast Cancer

DeMichele

Chodosh

2015

Clinical Cancer Research

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Endocrine resistance leads to recurrence and death from breast cancer. Animal models of endocrine resistance enable preclinical identification of efficacious therapeutic combinations and further our understanding of resistance. This strategy provides new insights into optimally targeting interactions between estrogen receptor (ESR-1) activity and the cell cycle by CDK4/6 inhibitors. See related article by Wardell et al., p. 5121 In this issue of Clinical Cancer Research, Wardell and colleagues utilized mouse models of endocrine therapy-resistant breast cancer to probe the relative efficacy of the cyclin-dependent kinase (CDK) 4/6 inhibitor, palbociclib, emerging endocrine agents, and their combination (1). Estrogen receptor (ER)-expressing breast cancer is the most common form of the disease, comprising nearly 80% of the more than 200,000 new cases diagnosed annually. While highly treatable by therapies that block ER signaling or prevent the production of its ligand, estrogen, resistance to endocrine therapy is universal in the metastatic setting and is also thought to be a common mechanism of recurrence in early-stage disease. The frequent occurrence of therapeutic resistance, coupled with the unparalleled high prevalence of this malignancy, mandates new approaches to overcoming endocrine resistance if continued improvements in survival are to be achieved.Current therapies targeting ER function include depletion of endogenous estrogens through aromatase-inhibition (AI), as well as blockade of estrogen binding to ER by selective estrogen receptor modulators (SERMS) and/or degraders (SERDS). Although these approaches are highly effective for some cancers, alterations resulting in estrogen-independent nuclear signaling or activation of escape pathways engender resistance. For example, activating mutations in ESR1 can render ER signaling ligandindependent (2). Similarly, changes in ER coactivators and corepressors can enable growth of ER þ cells despite low levels of estrogen.Alternative resistance mechanisms involve ER-driven activation of oncogenic signaling pathways, including the PI3K/Akt/mTOR pathway (3), and interactions with the core program that controls proliferation and cell cycle progression. These include inhibition or inactivation of negative regulators of the cell cycle, including RB family members, as well as amplification and upregulation of cell cycle-promoting oncogenes, such as cyclin D1 (CCND1) and c-myc (4). CCND1 drives RB inactivation and cell cycle progression by complexing with the cyclin-dependent kinases, CDK4 and CDK6. Given that ER activation, among other stimuli, can induce c-myc and CCND1 expression (5), CDK4 and CDK6 represent a nexus of signaling between the ER pathway and growth-promoting pathways in the cell. More recent data suggest that CDK4 and CDK6 can also regulate levels of steroid-metabolizing enzymes, including the AKR1C family, influencing the estrogenic state of breast tumors (6).Enter the new class of oral, highly selective CDK 4/6 inhibitors, including palbociclib (...

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Modulated Expression of Genes Encoding Estrogen Metabolizing Enzymes by G1-Phase Cyclin-Dependent Kinases 6 and 4 in Human Breast Cancer Cells

Cited by 6 publications

References 48 publications

Cyclin-Dependent Kinases 4/6 Inhibitors in Breast Cancer: Current Status, Resistance, and Combination Strategies

Cyclin-Dependent Kinases 4/6 Inhibitors in Breast Cancer: Current Status, Resistance, and Combination Strategies

Effect of Wnt5a on drug resistance in estrogen receptor-positive breast cancer

“Braking” the Cycle of Resistance in Endocrine Therapy for Breast Cancer

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