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Statins and endocrine resistance in breast cancer

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Cancer Drug resistance 2021年第2期4卷 356-364页

作者： Tara Hyder Juan Luis Gomez Marti Azadeh Nasrazadani Adam M.Brufsky University of Pittsburgh Physicians PittsburghPA 15213USA Department of Pathology University of Pittsburgh School of MedicinePittsburghPA 15213USA UPMC Hillman Cancer Center Magee Women's HospitalPittsburghPA 15213USA.

Most breast cancers are hormone-receptor positive(HR+).However,more women eventually die from HR+breast cancer than from either HER2+or triple negative breast *** therapies continue to be the mainstay of *** 40%of these cases,recurrences in early-stage disease and progression in the metastatic setting are largely a function of the development of endocrine resistance.A multitude of mediators and pathways have been associated with endocrine resistance in breast cancer including the mevalonate pathway,which is integral to cholesterol *** mevalonate pathway and the downstream activation of associated cytoplasmic pathways including PI3K-AKT-mTOR and RAS-MEK-ERK have been known to affect cancer cell proliferation,cell survival,cell invasion,and *** are important mechanisms leading to the inevitable development of endocrine resistance in HR+breast *** are a class of drugs that inhibits HMG-CoA reductase,an enzyme in the mevalonate pathway that plays a central role in cholesterol *** vitro and in vitro studies suggest that the role of statins in blocking the mevalonate pathway effectively disrupts downstream pathways involved in estrogen receptor expression and cellular processes such as cell survival,proliferation,stress,cell cycle,inhibition of apoptosis,and *** these key mechanisms heralds a role for statins in the prevention of endocrine resistance.

关键词： Statin HMGCR endocrine resistance autophagy PI3K mTOR

Advances in endocrine and targeted therapy for hormone-receptorpositive,human epidermal growth factor receptor 2-negative advanced breast cancer

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Chinese Medical Journal 2020年第9期133卷 1099-1108页

作者： Le-Sang Shen Xiao-Yan Jin Xu-Meng Wang Lai-Zhen Tou Jian Huang Department of Breast Surgery The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province HangzhouZhejiang 310009China Department of Surgical Oncology Zhejiang Taizhou Municipal HospitalTaizhouZhejiang 318000China Department of Surgical Oncology the First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310003China

Nearly 70%of breast cancer(BC)is hormone-receptor(HR)-positive,human epidermal growth factor receptor 2(HER2)-negative,and endocrine therapy is the mainstay of treatment for this ***,intrinsic or acquired endocrine resistance can occur during the endocrine *** on insights of endocrine resistance mechanisms,a number of targeted therapies have been and continue to be *** regard to HR-positive,HER2-negative advanced BC,aromatase inhibitor(AI)is superior to tamoxifen,and fulvestrant is a better option for patients previously exposed to endocrine *** drugs,such as cyclindependent kinases(CDK)4/6 inhibitors,mammalian target of rapamycin(mTOR)inhibitors,phosphoinositide-3-kinase(PI3K)inhibitors,and histone deacetylase(HDAC)inhibitors,play a significant role in the present and show a promising *** the application of CDK4/6 inhibitors becoming common,mechanisms of acquired resistance to them should also be taken into consideration.

关键词： endocrine therapy Advanced breast cancer endocrine resistance Targeted therapy

Oxidative stress and redox signaling in CRPC progression: therapeutic potential of clinically-tested Nrf2-activators

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Cancer Drug resistance 2021年第1期4卷 96-124页

作者： Debasis Mondal Devin Narwani Shahnawaz Notta Dawood Ghaffar Nikhil Mardhekar Syed S.A.Quadri Debusk College of Osteopathic Medicine Lincoln Memorial UniversityKnoxvilleTN 37932USA

Androgen deprivation therapy(ADT)is the mainstay regimen in patients with androgen-dependent prostate cancer(PCa).However,the selection of androgen-independent cancer cells leads to castrate resistant prostate cancer(CRPC).The aggressive phenotype of CRPC cells underscores the need to elucidate mechanisms and therapeutic strategies to suppress CRPC *** ADT,the activation of androgen receptor(AR)transcription factor continues via crosstalk with parallel signaling *** of how these signaling cascades are initiated and amplified post-ADT is *** deprivation can increase oxidative stress and the resultant reactive oxygen species(ROS)may activate both AR and non-AR ***,ROS-induced inflammatory cytokines may further amplify these redox signaling pathways to augment AR ***,clinical trials using ROS quenching small molecule antioxidants have not suppressed CRPC progression,suggesting that more potent and persistent suppression of redox signaling in CRPC cells will be *** transcription factor Nrf2 increases the expression of numerous antioxidant enzymes and downregulates the function of inflammatory transcription factors,e.g.,nuclear factor kappa *** documented that Nrf2 overexpression can suppress AR-mediated transcription in CRPC cell ***,two Nrf2 activating agents,sulforaphane(a phytochemical)and bardoxolone-methyl(a drug in clinical trial)suppress AR levels and sensitize CRPC cells to *** observations implicate the benefits of potent Nrf2-activators to suppress the lethal signaling cascades that lead to CRPC *** review article will address the redox signaling networks that augment AR signaling during PCa progression to CRPC,and the possible utility of Nrf2-activating agents as an adjunct to ADT.

关键词： Prostate cancer androgen receptor hormone therapy endocrine resistance oxidative stress redox signaling Nrf2 Nrf2-activators

Role of Yanghe Huayan Decoction in ER-PI3K/Akt/mTOR pathway of endocrine-resistant breast cancer cells with low mTOR expression

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Journal of Hainan Medical University 2020年第14期26卷 27-31页

作者： Xue Sun Xi-Xi Xu Xing-Yu Wang Run-Jia Luo Jing-Wei Li College of traditional Chinese medicine Shandong University of traditional Chinese medicineJinanShandong250014 The first clinical college of Shandong University of traditional Chinese medicine JinanShandong250014 Department of breast and thyroid surgery Affiliated Hospital of Shandong University of traditional Chinese medicineJinanShandong250014

Objective:To study the mechanism of action of Yanghe Huayan Decoction on endocrine-resistant cells(MCF-7R/mTOR cells)with low expression of mTOR;Methods:CCK-8 assay and cell clone assay were used to detect cell proliferation and clonal ability,and flow cytometry was used to detect cell *** changes of cytokines in ER-PI3K/Akt/mTOR signaling pathway were analyzed by blot and ***:Yanghe Huayan Decoction could significantly affect the proliferation(p<0.05)and cloning ability(p<0.05)of MCF-7R/mTOR cells,promote cell apoptosis(p<0.01),and downregulate the expression of ER,PI3K,AKT,mTOR and p-mTOR(p<0.05).Conclusion:Yanghe Huayan Decoction can regulate the ER-PI3K/Akt/mTOR signaling pathway with multiple targets,and the use of combined mTOR inhibitors can regulate the ER-PI3K/Akt/mTOR signaling pathway more significantly.

关键词： Yanghe Huayan Decoction Breast cancer endocrine resistance Low-level expression of Mtor ER-PI3K/Akt/mTOR

CDK4/6 inhibitors in the treatment of hormone receptor-positive, HER2-negative advanced breast cancer

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Drug Combination Therapy 2020年第1期2卷 25-33页

作者： Xue Yang Department of Medicat Oncotogy Tianjin Medicat University Generat HospitalTianjin 300052China

endocrine therapy(ET)is the therapy backbone of hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negati ve advanced breast ***,there are about 20%HR positive patients with no response to ET due to primary or acquired ET *** this background,many agents have been studied to overcome ET resistance and of which the important agents are cyclin-dependent kinase 4/6(CDK4/6)*** prognosis of advanced breast cancer has been improved by combing ET with CDK4/6 *** this review,we mainly focused on the CDK4/6 inhibitors in the treatment of HR-positive,HER2-negative advanced breast cancer and discussed the action mechanisms of CDK4/6 inhibitors alone or combined with *** also summarized several molecular features that would predict response or resistance to CDK4/6 *** addition,we put forward possible strategies to overcome CDK4/6 inhibitor resistance according to the latest research.

关键词： Breast cancer CDK4/6 inhibitors endocrine resistance Palbociclib Ribociclib Abemaciclib