Targeting Hypoxia Sensitizes TNBC to Cisplatin and Promotes Inhibition of Both Bulk and Cancer Stem Cells

Sulaiman, Andrew; McGarry, Sarah; Chambers, Jason; Al-Kadi, Emil; Phan, Alexandra; Li, Li; Mediratta, Karan; Dimitroulakos, Jim; Addison, Christina L.; Li, Xuguang; Wang, Lisheng

doi:10.3390/ijms21165788

Cited by 13 publications

(9 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is therefore imperative to revalidate the existing strategies used for cancer treatment and find new treatment methods based on killing of cancer cells targeted at the genetic level 39–41 . Cisplatin, the anthracycline doxorubicin, and the taxane docetaxel are commonly used drugs for BC treatment, and are often used in combination with multiple drugs to obtain better curative effects 42–44 . However, BC cells develop drug resistance with extended chemotherapy time, which in turn greatly reduces the effect of chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of cannabinoid receptor 2 is associated with human breast cancer proliferation, apoptosis, chemosensitivity and prognosis via the PI3K/Akt/mTOR signaling pathway

et al. 2023

View full text Add to dashboard Cite

Introduction The cannabinoid receptor 2 (CB2) is mainly involved in the immune system. However, although CB2 has been reported to play an anti‐tumor function in breast cancer (BC), its specific mechanism in BC remains unclear. Methods We examined the expression and prognostic significance of CB2 in BC tissues by qPCR, second‐generation sequencing, western blot, and immunohistochemistry. We assessed the impacts of overexpression and a specific agonist of CB2 on the growth, proliferation, apoptosis, and drug resistance of BC cells in vitro and in vivo using CCK‐8, flow cytometry, TUNEL staining, immunofluorescence, tumor xenografts, western blot, and colony formation assays. Results CB2 expression was significantly lower in BC compared with paracancerous tissues. It was also highly expressed in benign tumors and ductal carcinoma in situ, and its expression was correlated with prognosis in BC patients. CB2 overexpression and treatment of BC cells with a CB2 agonist inhibited proliferation and promoted apoptosis, and these actions were achieved by suppressing the PI3K/Akt/mTOR signaling pathway. Moreover, CB2 expression was increased in MDA‐MB‐231 cell treated with cisplatin, doxorubicin, and docetaxel, and sensitivity to these anti‐tumor drugs was increased in BC cells overexpressing CB2. Conclusions These findings reveal that CB2 mediates BC via the PI3K/Akt/mTOR signaling pathway. CB2 could be a novel target for the diagnosis and treatment of BC.

show abstract

Section: Discussionmentioning

confidence: 99%

Overexpression of cannabinoid receptor 2 is associated with human breast cancer proliferation, apoptosis, chemosensitivity and prognosis via the PI3K/Akt/mTOR signaling pathway

et al. 2023

View full text Add to dashboard Cite

show abstract

“…[19] The development of the hypoxic microenvironment inside the tumor is accelerated by the increased oxygen consumption of the tumor cells and the insufficient oxygen delivery provided by the tumor microvasculature. [20] TNBC cells produce reactive oxygen species (ROS) and nitric oxide (NO) in response to acute and ongoing inflammation as well as the upkeep of chronic hypoxia. [21] Inflammatory mediators are produced as a result of tumor-intrinsic gene mutations, inactivation, and antitumor therapy for TNBC.…”

Section: Structure Of Hif-1mentioning

confidence: 99%

Hypoxia-mediated activation of hypoxia-inducible factor-1α in triple-negative breast cancer: A review

Liu,

Bai,

et al. 2023

Medicine

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) that is highly aggressive and hypoxic compared with other subtypes. The role of hypoxia-inducible factor 1α (HIF-1α) as a key hypoxic transcription factor in oncogenic processes has been extensively studied. Recently, it has been shown that HIF-1α regulates the complex biological processes of TNBC, such as glycolysis, angiogenesis, invasion and metastasis, BC stem cells enrichment, and immune escape, to promote TNBC survival and development through the activation of downstream target genes. This article discusses the expression of the HIF-1α transcription factor in TNBC and the Hypoxia-mediated activation of hypoxia-inducible factor-1α in triple-negative BC. It offers a fresh approach to clinical research and treatment for TNBC.

show abstract

“…The inhibition of the hypoxia-induced carbonic anhydrase IX in TNBC cell lines impaired their ability to form new vasculature and mammospheres as well as metastasize [ 61 ]. Hence, targeting hypoxia in TNBC has been shown to increase tumor sensitivity to chemotherapies such as cisplatin, doxorubicin, and 5-fluorouracil [ 62 , 63 , 64 , 65 ].…”

Section: Double Trouble: Hypoxia In Triple-negative Breast Cancermentioning

confidence: 99%

Adaptation to Hypoxia May Promote Therapeutic Resistance to Androgen Receptor Inhibition in Triple-Negative Breast Cancer

Jinna

Rida²,

Smart³

et al. 2022

IJMS

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC) surpasses other BC subtypes as the most challenging to treat due to its lack of traditional BC biomarkers. Nearly 30% of TNBC patients express the androgen receptor (AR), and the blockade of androgen production and AR signaling have been the cornerstones of therapies for AR-positive TNBC. However, the majority of women are resistant to AR-targeted therapy, which is a major impediment to improving outcomes for the AR-positive TNBC subpopulation. The hypoxia signaling cascade is frequently activated in the tumor microenvironment in response to low oxygen levels; activation of the hypoxia signaling cascade allows tumors to survive despite hypoxia-mediated interference with cellular metabolism. The activation of hypoxia signaling networks in TNBC promotes resistance to most anticancer drugs including AR inhibitors. The activation of hypoxia network signaling occurs more frequently in TNBC compared to other BC subtypes. Herein, we examine the (1) interplay between hypoxia signaling networks and AR and (2) whether hypoxia and hypoxic stress adaptive pathways promote the emergence of resistance to therapies that target AR. We also pose the well-supported question, “Can the efficacy of androgen-/AR-targeted treatments be enhanced by co-targeting hypoxia?” By critically examining the evidence and the complex entwinement of these two oncogenic pathways, we argue that the simultaneous targeting of androgen biosynthesis/AR signaling and hypoxia may enhance the sensitivity of AR-positive TNBCs to AR-targeted treatments, derail the emergence of therapy resistance, and improve patient outcomes.

show abstract

Targeting Hypoxia Sensitizes TNBC to Cisplatin and Promotes Inhibition of Both Bulk and Cancer Stem Cells

Cited by 13 publications

References 79 publications

Overexpression of cannabinoid receptor 2 is associated with human breast cancer proliferation, apoptosis, chemosensitivity and prognosis via the PI3K/Akt/mTOR signaling pathway

Overexpression of cannabinoid receptor 2 is associated with human breast cancer proliferation, apoptosis, chemosensitivity and prognosis via the PI3K/Akt/mTOR signaling pathway

Hypoxia-mediated activation of hypoxia-inducible factor-1α in triple-negative breast cancer: A review

Adaptation to Hypoxia May Promote Therapeutic Resistance to Androgen Receptor Inhibition in Triple-Negative Breast Cancer

Contact Info

Product

Resources

About