Recent advances in the personalized treatment of estrogen receptor-positive breast cancer with tamoxifen: a focus on pharmacogenomics

Slanař, Ondřej; Hronová, Karolína; Bartošová, Olga; Šíma, Martin

doi:10.1080/17425255.2021.1865310

Cited by 9 publications

(6 citation statements)

References 148 publications

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“…Estrogens exert their proliferative effects by bind to estrogen receptors. Two nuclear ERs, ER α and ER β , are relatively well studied for their roles in breast cancers [ 25 ] [ 26 ] [ 27 ] [ 28 ] [ 29 ]. G Protein-coupled ER (GPER) is a plasma membrane protein, resulting in intracellular calcium mobilization and synthesis of phosphatidylinositol (3,4,5)-trisphosphate.…”

Section: Discussionmentioning

confidence: 99%

Breast Cancer MCF-7 Cell Spheroid Culture for Drug Discovery and Development

Chen¹,

Liu²,

Yan³

2022

JCT

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In vitro 3D cancer spheroids (tumoroids) exhibit a drug resistance profile similar to that found in solid tumors. 3D spheroid culture methods recreate more physiologically relevant microenvironments for cells. Therefore, these models are more appropriate for cancer drug screening. We have recently developed a protocol for MCF-7 cell spheroid culture, and used this method to test the effects of different types of drugs on this estrogen-dependent breast cancer cell spheroid. Our results demonstrated that MCF-7 cells can grow spheroid in medium using a low attachment plate. We managed to grow one spheroid in each well, and the spheroid can grow over a month, the size of the spheroid can grow over a hundred times in volume. Our targeted drug experimental results suggest that estrogen sulfotransferase, steroid sulfatase, and G protein-coupled estrogen receptor may play critical roles in MCF-7 cell spheroid growth, while estrogen receptors α and β may not play an essential role in MCF-7 spheroid growth. Organoids are the miniatures of in vivo tissues and reiterate the in vivo microenvironment of a specific organ, best fit for the in vitro studies of diseases and drug development. Tumoroid, developed from cancer cell lines or patients’ tumor tissue, is the best in vitro model of in vivo tumors. 3D spheroid technology will be the best future method for drug development of cancers and other diseases. Our reported method can be developed clinically to develop personalized drugs when the patient’s tumor tissues are used to develop a spheroid culture for drug screening.

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Section: Discussionmentioning

confidence: 99%

Breast Cancer MCF-7 Cell Spheroid Culture for Drug Discovery and Development

Chen¹,

Liu²,

Yan³

2022

JCT

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“…Last, the approach in this study is focused on the PGx of the pharmacokinetic marker CYP2D6. Nonetheless, PGx of pharmacodynamic targets can also play a role in variability in drug response (2,56,57). This field is currently less well understood because of the difficulties associated with phenotype definitions.…”

Section: Discussionmentioning

confidence: 99%

Toward predicting CYP2D6-mediated variable drug response from CYP2D6 gene sequencing data

et al. 2021

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Pharmacogenomics is a key component of personalized medicine that promises safer and more effective drug treatment by individualizing drug choice and dose based on genetic profiles. In clinical practice, genetic biomarkers are used to categorize patients into *-alleles to predict CYP450 enzyme activity and adjust drug dosages accordingly. However, this approach leaves a large part of variability in drug response unexplained. Here, we present a proof-of-concept approach that uses continuous-scale (instead of categorical) assignments to predict enzyme activity. We used full CYP2D6 gene sequences obtained with long-read amplicon-based sequencing and cytochrome P450 (CYP) 2D6–mediated tamoxifen metabolism data from a prospective study of 561 patients with breast cancer to train a neural network. The model explained 79% of interindividual variability in CYP2D6 activity compared to 54% with the conventional *-allele approach, assigned enzyme activities to known alleles with previously reported effects, and predicted the activity of previously uncharacterized combinations of variants. The results were replicated in an independent cohort of tamoxifen-treated patients (model R2 adjusted = 0.66 versus *-allele R2 adjusted = 0.35) and a cohort of patients treated with the CYP2D6 substrate venlafaxine (model R2 adjusted = 0.64 versus *-allele R2 adjusted = 0.55). Human embryonic kidney cells were used to confirm the effect of five genetic variants on metabolism of the CYP2D6 substrate bufuralol in vitro. These results demonstrate the advantage of a continuous scale and a completely phased genotype for prediction of CYP2D6 enzyme activity and could potentially enable more accurate prediction of individual drug response.

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“…An ideal SERM can thus be utilized for the treatment and prevention of breast cancer (Makar et al, 2020) and osteoporosis (Goldstein, 2022) or to provide relief of hot flashes and other menopause symptoms (Mehedintu et al, 2021). The classical SERM, tamoxifen, is a selective ER blocker in the breast and is an effective agent for treating breast cancer (Cha et al, 2021;Slanař et al, 2021). It has also been indicated to prevent bone loss (Genant, 2011) and provide cardioprotective benefits (Ebrahimi et al, 2020).…”

Section: Estrogen Receptormentioning

confidence: 99%

The potential effects of isoflavones on nuclear receptor modulation in bone remodeling: A review

Hairi¹,

Mustafa²,

Jayusman³

et al. 2023

J App Pharm Sc

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Isoflavones are plant-based compounds that act as phytoestrogens by mimicking the action of estrogen. Osteoblasts and osteoclasts are the key cells for bone remodeling, a process that includes bone proliferation, differentiation, deposition, and resorption. Studies have demonstrated that isoflavones, a class of flavonoids found almost exclusively in soybeans, could prevent bone loss. Recent findings revealed that isoflavones could activate nuclear receptors (NRs) and regulate bone formation and resorption processes. This current research discussed the principal actions of isoflavones mediated by NRs on bone remodeling such as steroid receptors (estrogen receptor, estrogen-related receptor, and androgen receptor) and metabolic receptors including peroxisome proliferator-activated receptor-γ. Isoflavones modulate osteogenesis by fine-tuning physiological responses on NR sensors and their transcriptional networks. Hence, this present review will dive deep into the use of several isoflavones as potential osteoporosis treatment through NR-controlling gene regulation.

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Recent advances in the personalized treatment of estrogen receptor-positive breast cancer with tamoxifen: a focus on pharmacogenomics

Cited by 9 publications

References 148 publications

Breast Cancer MCF-7 Cell Spheroid Culture for Drug Discovery and Development

Breast Cancer MCF-7 Cell Spheroid Culture for Drug Discovery and Development

Toward predicting CYP2D6-mediated variable drug response from CYP2D6 gene sequencing data

The potential effects of isoflavones on nuclear receptor modulation in bone remodeling: A review

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