Chemoresistance mechanisms of breast cancer and their countermeasures

Ji, Xiwei; Lü, Yuan; Tian, Huifang; Meng, Xiangrui; Wei, Min-Ji; Cho, William C.

doi:10.1016/j.biopha.2019.108800

Cited by 257 publications

(214 citation statements)

References 116 publications

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“…Chemoresistance is the leading cause of therapy failure and high mortality rates in breast cancer 2 . The drug efflux pump ABCB1 plays a key role in promoting chemoresistance by actively effluxing a broad range of chemotherapeutic agents from tumor cells 2,4,5 . Attempts at inhibiting ABCB1 directly have failed clinically due to disruption of normal tissue and lack of specificity 7 .…”

Section: Discussionmentioning

confidence: 99%

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ROR1 regulates chemoresistance in Breast Cancer via modulation of drug efflux pump ABCB1

Fultang

Illendula

Lin

et al. 2020

Sci Rep

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Chemoresistance is one of the leading causes of mortality in breast cancer (BC). Understanding the molecules regulating chemoresistance is critical in order to combat chemoresistant BC. Drug efflux pump ABCB1 is overexpressed in chemoresistant neoplasms where it effluxes various chemotherapeutic agents from cells. Because it is expressed in normal and cancerous cells alike, attempts at targeting ABCB1 directly have failed due to low specificity and disruption of normal tissue. A proposed method to inhibit ABCB1 is to target its cancer-specific, upstream regulators, mitigating damage to normal tissue. Few such cancer-specific upstream regulators have been described. Here we characterize ROR1 as an upstream regulator of ABCB1. ROR1 is highly expressed during development but not expressed in normal adult tissue. It is however highly expressed in several cancers. ROR1 is overexpressed in chemoresistant BC where it correlates with poor therapy response and tumor recurrence. Our data suggests, ROR1 inhibition sensitizes BC cells to chemo drugs. We also show ROR1 regulates ABCB1 stability and transcription via MAPK/ERK and p53. Validating our overall findings, inhibition of ROR1 directly correlated with decreased efflux of chemo-drugs from cells. Overall, our results highlight ROR1's potential as a therapeutic target for multidrug resistant malignancies. ROR1 knockdown potentiates DNA damage induced by chemo drugs.A mechanism of action common to both Pt-based and anthracycline chemotherapeutic agents is induction of DNA double stranded breaks leading to cell death 19 . We thus sought to investigate if ROR1 inhibition would promote chemo-induced DNA double strand breaks. We treated cells transfected with either ROR1 siRNA or control RNA, with Doxorubicin or Cisplatin, and monitored γH2a.x, a marker for DNA double strand breaks via immunofluorescence ( Fig. 3A, Supplementary Fig. 2). We observed potentiation of DNA double strand breaks induced by both drugs in cells where ROR1 was knocked down. γH2a.x foci counts were higher in the siROR1+ (Dox or Cis) groups compared to the siROR1-only and drug-only treatment groups (Fig. 3B). We similarly observed an increase in γH2a.x expression (mean fluorescence intensity) in Cis/Dox treated cells after ROR1 knockdown compared to the control group (Fig. 3C). Altogether, these data suggest ROR1 inhibition promotes chemo drug-induced DNA damage. Scientific RepoRtS |(2020) 10:1821 | https://doi.

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Section: Discussionmentioning

confidence: 99%

“…The ABC family of ATP-dependent drug effluxers, most notably ABCB1/MDR-1, have been shown to play a major role in chemoresistance 2,4,5 . ABCB1 can transport a variety of substrates out of cells via ATP-hydrolysis 2,5,6 . In cancer, ABCB1 actively effluxes a broad range of chemotherapeutic agents from cells leading to multidrug resistance 6 .…”

mentioning

confidence: 99%

ROR1 regulates chemoresistance in Breast Cancer via modulation of drug efflux pump ABCB1

Fultang

Illendula

Lin

et al. 2020

Sci Rep

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“…Plasma could be pooled in batches to attenuate this effect in cell lines where matching plasma is not available. Additionally, further studies will look into combination therapies of chemotherapeutic drugs, natural compounds, or monoclonal antibodies in order to provide more effective strategies for treating BCa due to the resistance of BCa cells and the various side effects of current treatments [98,99]. Drug efflux mechanisms will be further evaluated in HuP3D cultures, due to the fact that an elevated efflux of anticancer agents, leading to decreased intracellular drug accumulation, has been considered to be the major reason for chemotherapy resistance [99,100].…”

Section: Discussionmentioning

confidence: 99%

Human Plasma-Derived 3D Cultures Model Breast Cancer Treatment Responses and Predict Clinically Effective Drug Treatment Concentrations

Calar

Plesselova

Bhattacharya

et al. 2020

Cancers

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Lack of efficacy and a low overall success rate of phase I-II clinical trials are the most common failures when it comes to advancing cancer treatment. Current drug sensitivity screenings present several challenges including differences in cell growth rates, the inconsistent use of drug metrics, and the lack of translatability. Here, we present a patient-derived 3D culture model to overcome these limitations in breast cancer (BCa). The human plasma-derived 3D culture model (HuP3D) utilizes patient plasma as the matrix, where BCa cell lines and primary BCa biopsies were grown and screened for drug treatments. Several drug metrics were evaluated from relative cell count and growth rate curves. Correlations between HuP3D metrics, established preclinical models, and clinical effective concentrations in patients were determined. HuP3D efficiently supported the growth and expansion of BCa cell lines and primary breast cancer tumors as both organoids and single cells. Significant and strong correlations between clinical effective concentrations in patients were found for eight out of ten metrics for HuP3D, while a very poor positive correlation and a moderate correlation was found for 2D models and other 3D models, respectively. HuP3D is a feasible and efficacious platform for supporting the growth and expansion of BCa, allowing high-throughput drug screening and predicting clinically effective therapies better than current preclinical models.

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“… 29 Despite this success, although anthracycline-based regimens have become standard of care, chemoresistance is still a major challenge. 30 Thus, improved biomarkers are required to better inform and direct appropriate therapies, especially for high-risk patients. The role of the tumor microenvironment in the control of cancer progression is well established, 31 but using a combination of molecular and morphologic tumor microenvironment–based biomarkers as prognostic indicators has been poorly explored.…”

Section: Discussionmentioning

confidence: 99%

Association of Low Tumor Endothelial Cell pY397–Focal Adhesion Kinase Expression With Survival in Patients With Neoadjuvant-Treated Locally Advanced Breast Cancer

et al. 2020

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Key Points Question Are phosphorylated–focal adhesion kinase (pY397-FAK) expression levels in endothelial or tumor cells and tumor blood vessel density associated with response to chemotherapy and relapse-free survival after neoadjuvant chemotherapy in patients with locally advanced breast cancer? Findings In this prognostic study of 82 women with stage IIA to IIIC locally advanced breast cancer, low endothelial cell pY397-FAK expression levels in prechemotherapy core biopsies were associated with sensitivity to neoadjuvant chemotherapy and improved 5-year relapse-free survival. Combined analysis of high endothelial cell pY397-FAK, high tumor cell pY397-FAK, and high blood vessel density appeared to identify a high-risk population. Meaning The findings of this study suggest that endothelial cell pY397-FAK levels could be used as a clinical tool for indicating response to neoadjuvant chemotherapy.

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Chemoresistance mechanisms of breast cancer and their countermeasures

Cited by 257 publications

References 116 publications

ROR1 regulates chemoresistance in Breast Cancer via modulation of drug efflux pump ABCB1

ROR1 regulates chemoresistance in Breast Cancer via modulation of drug efflux pump ABCB1

Human Plasma-Derived 3D Cultures Model Breast Cancer Treatment Responses and Predict Clinically Effective Drug Treatment Concentrations

Association of Low Tumor Endothelial Cell pY397–Focal Adhesion Kinase Expression With Survival in Patients With Neoadjuvant-Treated Locally Advanced Breast Cancer

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