The role of hypoxia-inducible factor-1 alpha in multidrug-resistant breast cancer

Yong, Liyun; Tang, Sing Hai; Yu, Haixin; Zhang, Hongyi; Zhang, Yi; Yuan, Wei; Cai, Fengfeng

doi:10.3389/fonc.2022.964934

Cited by 34 publications

(15 citation statements)

References 115 publications

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“…Vascular heterogeneity may induce a multiple drug resistant-like phenotype since inadequate vascularity may prevent many drugs, independent of their chemical structure or mechanism of action, from reaching some areas of a tumor. Regions that are poorly vascularized may also be hypoxic, with induction of hypoxia stress responses already active in surviving cells in a manner that may also confer resistance to some drugs that reach these hypoxic cells (163)(164)(165).…”

Section: Drug Response Heterogeneitymentioning

confidence: 99%

The complex nature of heterogeneity and its roles in breast cancer biology and therapeutic responsiveness

et al. 2023

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Heterogeneity is a complex feature of cells and tissues with many interacting components. Depending on the nature of the research context, interacting features of cellular, drug response, genetic, molecular, spatial, temporal, and vascular heterogeneity may be present. We describe the various forms of heterogeneity with examples of their interactions and how they play a role in affecting cellular phenotype and drug responses in breast cancer. While cellular heterogeneity may be the most widely described and invoked, many forms of heterogeneity are evident within the tumor microenvironment and affect responses to the endocrine and cytotoxic drugs widely used in standard clinical care. Drug response heterogeneity is a critical determinant of clinical response and curative potential and also is multifaceted when encountered. The interactive nature of some forms of heterogeneity is readily apparent. For example, the process of metastasis has the properties of both temporal and spatial heterogeneity within the host, whereas each individual metastatic deposit may exhibit cellular, genetic, molecular, and vascular heterogeneity. This review describes the many forms of heterogeneity, their integrated activities, and offers some insights into how heterogeneity may be understood and studied in the future.

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Section: Drug Response Heterogeneitymentioning

confidence: 99%

The complex nature of heterogeneity and its roles in breast cancer biology and therapeutic responsiveness

et al. 2023

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Section: Nf-κb In Bcmentioning

confidence: 99%

“…When the oxygen (O 2 ) levels in the tumor microenvironment fall below 5–10 mmHg, it is referred to as hypoxia, which is characterized by discrepancies in O 2 absorption and consumption induced by the uncontrolled proliferation of cancer tissues [ 79 ]. It should be noted that hypoxia is a characteristic of many solid tumors, including BC, and that it is connected to cell survival, proliferation, angiogenesis, and metastasis [ 79 ]. Importantly, hypoxia promotes the activities of clinically significant transcription factors (HIFs), which are represented by: (1) a heterodimer structure composed of O 2 -senstive α subunit-dependent transcription factors―HIF-1α, HIF-2α, and HIF-3α―containing an O 2 -dependent degradation domain (ODDD) that mediates the proteasomal destruction of the HIFs through the inhibition of the N-terminal domain (N-TAD) and (2) HIF-1β transcription factors that do not require an α subunit [ 79 , 80 ].…”

Section: Nf-κb In Bcmentioning

confidence: 99%

“…It should be noted that hypoxia is a characteristic of many solid tumors, including BC, and that it is connected to cell survival, proliferation, angiogenesis, and metastasis [ 79 ]. Importantly, hypoxia promotes the activities of clinically significant transcription factors (HIFs), which are represented by: (1) a heterodimer structure composed of O 2 -senstive α subunit-dependent transcription factors―HIF-1α, HIF-2α, and HIF-3α―containing an O 2 -dependent degradation domain (ODDD) that mediates the proteasomal destruction of the HIFs through the inhibition of the N-terminal domain (N-TAD) and (2) HIF-1β transcription factors that do not require an α subunit [ 79 , 80 ]. Significantly, after HIF-1α overexpression, it binds to p300/CBP and activates various genes in favor of BC by binding to a specific gene region called the hypoxia-responsive element ( HRE ).…”

Section: Nf-κb In Bcmentioning

confidence: 99%

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The NF-κB Transcriptional Network Is a High-Dose Vitamin C-Targetable Vulnerability in Breast Cancer

et al. 2023

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Breast cancer (BC) is the most common cancer type among women with a distinct clinical presentation, but the survival rate remains moderate despite advances in multimodal therapy. Consequently, a deeper understanding of the molecular etiology is required for the development of more effective treatments for BC. The relationship between inflammation and tumorigenesis is well established, and the activation of the pro-inflammatory transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is frequently identified in BC. Constitutive NF-κB activation is linked to cell survival, metastasis, proliferation, and hormonal, chemo-, and radiotherapy resistance. Moreover, the crosstalk between NF-κB and other transcription factors is well documented. It is reported that vitamin C plays a key role in preventing and treating a number of pathological conditions, including cancer, when administered at remarkably high doses. Indeed, vitamin C can regulate the activation of NF-κB by inhibiting specific NF-κB-dependent genes and multiple stimuli. In this review, we examine the various NF-κB impacts on BC development. We also provide some insight into how the NF-κB network may be targeted as a potential vulnerability by using natural pro-oxidant therapies such as vitamin C.

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“…Over-expression of the multidrug resistance protein 1 (MDR1) is also associated with the resistance of taxane and anthracyclines, which are principle chemotherapeutic agents for TNBC treatment [ 12 ]. Both HIF-1α and HIF-2α are known to activate factors involved in pluripotency and regulate the stem cell phenotype, both in normal and cancer cells [ 8 , 13 , 14 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Estrogen Receptor β4 Regulates Chemotherapy Resistance and Induces Cancer Stem Cells in Triple Negative Breast Cancer

Bano

Stevens

Modi

et al. 2023

IJMS

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Triple Negative Breast Cancer (TNBC) has the worst prognosis among all breast cancers, and survival in patients with recurrence is rarely beyond 12 months due to acquired resistance to chemotherapy, which is the standard of care for these patients. Our hypothesis is that Estrogen Receptor β1 (ERβ1) increases response to chemotherapy but is opposed by ERβ4, which it preferentially dimerizes with. The role of ERβ1 and ERβ4 in influencing chemotherapy sensitivity has never been studied before. CRISPR/CAS9 was used to truncate ERβ1 Ligand Binding Domain (LBD) and knock down the exon unique to ERβ4. We show that the truncated ERβ1 LBD in a variety of mutant p53 TNBC cell lines, where ERβ1 ligand dependent function was inactivated, had increased resistance to Paclitaxel, whereas the ERβ4 knockdown cell line was sensitized to Paclitaxel. We further show that ERβ1 LBD truncation, as well as treatment with ERβ1 antagonist 2-phenyl-3-(4-hydroxyphenyl)-5,7-bis(trifluoromethyl)-pyrazolo[1,5-a] pyrimidine (PHTPP), leads to increase in the drug efflux transporters. Hypoxia Inducible Factors (HIFs) activate factors involved in pluripotency and regulate the stem cell phenotype, both in normal and cancer cells. Here we show that the ERβ1 and ERβ4 regulate these stem cell markers like SOX2, OCT4, and Nanog in an opposing manner; and we further show that this regulation is mediated by HIFs. We show the increase of cancer cell stemness due to ERβ1 LBD truncation is attenuated when HIF1/2α is knocked down by siRNA. Finally, we show an increase in the breast cancer stem cell population due to ERβ1 antagonist using both ALDEFLUORTM and SOX2/OCT4 response element (SORE6) reporters in SUM159 and MDA-MB-231 cell lines. Since most TNBC cancers are ERβ4 positive, while only a small proportion of TNBC patients are ERβ1 positive, we believe that simultaneous activation of ERβ1 with agonists and inactivation of ERβ4, in combination with paclitaxel, can be more efficacious and yield better outcome for chemotherapy resistant TNBC patients.

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The role of hypoxia-inducible factor-1 alpha in multidrug-resistant breast cancer

Cited by 34 publications

References 115 publications

The complex nature of heterogeneity and its roles in breast cancer biology and therapeutic responsiveness

The complex nature of heterogeneity and its roles in breast cancer biology and therapeutic responsiveness

The NF-κB Transcriptional Network Is a High-Dose Vitamin C-Targetable Vulnerability in Breast Cancer

Estrogen Receptor β4 Regulates Chemotherapy Resistance and Induces Cancer Stem Cells in Triple Negative Breast Cancer

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