Metabolic reprograming confers tamoxifen resistance in breast cancer

Mishra, Alok; Srivastava, Anshuman; Pateriya, Ankit; Tomar, Manendra Singh; Mishra, Anand; Shrivastava, Ashutosh

doi:10.1016/j.cbi.2021.109602

Cited by 43 publications

(34 citation statements)

References 113 publications

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“… 4 Although TAM represents a tremendous therapeutic breakthrough with great improvements in survival, not all patients benefit from its use. 5 Approximately 25% of patients do not respond to initial TAM treatment, and 40% of the responsive patients develop resistance. 5 This emergence of intrinsic and acquired resistance represents a substantial obstacle to patient life expectancy.…”

Section: Introductionmentioning

confidence: 99%

“… 5 Approximately 25% of patients do not respond to initial TAM treatment, and 40% of the responsive patients develop resistance. 5 This emergence of intrinsic and acquired resistance represents a substantial obstacle to patient life expectancy. 6 Therefore, exploration of new therapeutic strategies to enhance the efficacy of TAM by overcoming resistance in breast cancer cells is urgently needed.…”

Section: Introductionmentioning

confidence: 99%

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Baicalein resensitizes tamoxifen‐resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia‐inducible factor‐1α

Chen

Zhang

et al. 2021

Clinical & Translational Med

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Drug resistance is a major hurdle for the effectiveness of tamoxifen (TAM) to provide clinical benefit. Therefore, it is essential to identify a sensitizer that could be used to improve TAM efficacy in treating TAM‐resistant breast cancer. Here, we investigated the ability of baicalein to reverse TAM resistance. We found that baicalein increased the efficacy of TAM in inhibiting proliferation and inducing apoptosis of TAM‐resistant cells. It also enhanced the TAM‐induced growth reduction of resistant cells from NOD/SCID mouse mammary fat pads, without causing obvious systemic toxicity. Analyses using the CellMiner tool and the Kaplan–Meier plotter database showed that HIF‐1α expression was inversely correlated with TAM therapeutic response in NCI‐60 cancer cells and breast cancer patients. HIF‐1α expression was increased in TAM‐resistant cells due to an increase in mRNA levels and reduced ubiquitin‐mediated degradation. Baicalein reduced HIF‐1α expression by promoting its interaction with PHD2 and pVHL, thus facilitating ubiquitin ligase‐mediated proteasomal degradation and thereby suppressing the nuclear translocation, binding to the hypoxia‐response element, and transcriptional activity of HIF‐1α. As a result, baicalein downregulated aerobic glycolysis by restricting glucose uptake, lactate production, ATP generation, lactate/pyruvate ratio and expression of HIF‐1α‐targeted glycolytic genes, thereby enhancing the antiproliferative efficacy of TAM. Furthermore, baicalein interfered with HIF‐1α inhibition of mitochondrial biosynthesis, which increased mitochondrial DNA content and mitochondrial numbers, restored the generation of reactive oxygen species in mitochondria, and thus enhanced the TAM‐induced mitochondrial apoptotic pathway. The HIF‐1α stabilizer dimethyloxallyl glycine prevented the baicalein‐induced downregulation of glycolysis and mitochondrial biosynthesis and reduced the effects of baicalein on reversing TAM resistance. Our results indicate that baicalein is a promising candidate to help overcome TAM resistance by sensitizing resistant cells to TAM‐induced growth inhibition and apoptosis. The mechanism underlying the effects of baicalein consists of inhibition of HIF‐1α–mediated aerobic glycolysis and mitochondrial dysfunction.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Baicalein resensitizes tamoxifen‐resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia‐inducible factor‐1α

Chen

Zhang

et al. 2021

Clinical & Translational Med

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“…Many mechanisms have been described as being responsible for the escape of cancer cells from the cytotoxic effects of tamoxifen, including loss or deregulation of ERα expression and alterations of signaling pathways responsible for survival, proliferation, apoptosis, and stress responses (9,10,15,16,(19)(20)(21). Metabolic rewiring plays a crucial role in cellular growth, survival, and proliferation to generate an adequate amount of adenosine triphosphate (ATP) and to fuel the biosynthesis of macromolecules in breast cancer (22). There is evidence supporting the role of reprogramming lipid, glucose (23,24), and amino acid (25,26) metabolism in the resistance to endocrine therapy.…”

Section: Introductionmentioning

confidence: 99%

CRISPR/Cas9 screen reveals a role of purine synthesis for estrogen receptor α activity and tamoxifen resistance of breast cancer cells

Hany

Vafeiadou

Picard

2022

Preprint

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In breast cancer, resistance to endocrine therapies that target estrogen receptor α (ERα), such as tamoxifen and fulvestrant, remains a major clinical problem. Whether and how ERα+ breast cancers switch from being estrogen-dependent to -independent remains unclear. With a genome-wide CRISPR/Cas9 knockout screen, we identified new biomarkers and potential therapeutic targets of endocrine resistance. We demonstrate that high levels of PAICS, an enzyme involved in the de novo biosynthesis of purines, can shift the balance of ERα activity to be more estrogen-independent and tamoxifen-resistant. We indicate that this is due to an elevated activity of cAMP-activated protein kinase A and mammalian target of rapamycin, kinases known to phosphorylate ERα specifically and to stimulate its activity. Genetic or pharmacological targeting of PAICS sensitizes tamoxifen-resistant cells to tamoxifen. Based on these findings, we propose the combined targeting of PAICS and ERα as a new, effective, and potentially safe therapeutic regimen.

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“…[4] Endocrine-resistant breast cancer patients probably account for 40 % of all breast cancer patients. [5] Therefore, finding new therapies or drugs for tamoxifen-resistant breast cancer patients has great clinical significance. Recent studies have found that, Chinese herbs and their compounds are becoming alternative to oncotherapy.…”

Section: Introductionmentioning

confidence: 99%

“…Many ER+ breast cancer patients have benefited from tamoxifen, but the resistance to tamoxifen that develops over time with treatment may cause tumour recurrence and metastasis [4] . Endocrine‐resistant breast cancer patients probably account for 40 % of all breast cancer patients [5] . Therefore, finding new therapies or drugs for tamoxifen‐resistant breast cancer patients has great clinical significance.…”

Section: Introductionmentioning

confidence: 99%

Dihydrotanshinone I: A Target for STAT3 in the Therapy of Tamoxifen‐Resistant Breast Cancer

Zhu

Zheng

et al. 2022

ChemistrySelect

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Breast cancer is the most prevalent tumour in women. Over two-thirds of breast cancers are estrogen receptor (ER)-positive breast cancers. These breast cancer patients are prone to tamoxifen resistance during breast cancer treatment. There is still a lack of effective clinical treatment for tamoxifen-resistant breast cancer. Dihydrotanshinone I (DHTS) promotes various types of apoptosis in tumour cells. Our network pharmacology study revealed that DHTS has a strong binding capacity to STAT3. Tamoxifen-resistant breast cancers are often accompanied by STAT3 activation. However, there are no reports of DHTS for tamoxifen-resistant breast cancer. Subsequent in vitro experiments also confirmed that DHTS promoted apoptosis in MCF-7-TamR cells, down-regulated the performance of STAT3, pSTAT3, and BCL-2, and activated the production of apoptosisassociated PARP1 and cleaved caspase3. This process could be rescued by overexpression of BCL-2 downstream of STAT3 and was not rescued by either the cytokine EGF or the cytokine PDGF, which promote STAT3 phosphorylation. We hypothesized that DHTS targeting STAT3 promotes apoptosis in MCF-7-TamR cells, mainly by affecting STAT3 phosphorylation. Our research approach described above may provide new ideas for the treatment of tamoxifen-resistant breast cancer.

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Metabolic reprograming confers tamoxifen resistance in breast cancer

Cited by 43 publications

References 113 publications

Baicalein resensitizes tamoxifen‐resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia‐inducible factor‐1α

Baicalein resensitizes tamoxifen‐resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia‐inducible factor‐1α

CRISPR/Cas9 screen reveals a role of purine synthesis for estrogen receptor α activity and tamoxifen resistance of breast cancer cells

Dihydrotanshinone I: A Target for STAT3 in the Therapy of Tamoxifen‐Resistant Breast Cancer

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