Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance

Bekele, Raie; Venkatraman, Ganesh; Liu, Rong‐Zong; Tang, Xiaoyun; Mi, Si; Benesch, Matthew G.K.; Mackey, John R.; Godbout, Roseline; Curtis, Jonathan M.; McMullen, Todd; Brindley, David N.

doi:10.1038/srep21164

Cited by 96 publications

(72 citation statements)

References 81 publications

(107 reference statements)

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“…10) (29). This inflammatory cycle stimulates tumor growth and metastasis and produces resistance to various forms of chemotherapy that are used to treat breast cancer (30, 32, 33). Part of this chemoresistance depends on increased LPA signaling via LPA 1 receptors, which increases Nrf2 expression and the consequent synthesis of antioxidant proteins and multidrug resistance transporters (32).…”

Section: Discussionmentioning

confidence: 99%

“…LPA also protects cancer cells from the chemotherapeutic effects of pacitaxol (30), carboplatin (31), doxorubicin (32), and tamoxifen (33). Thus, the inhibition of LPA formation with ONO-8430506 decreased breast tumor growth in combination with doxorubicin in mice by approximately 75%, whereas doxorubicin alone had little effect on tumor growth, and ONO-8430506 alone decreased tumor growth by approximately 60%.…”

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confidence: 99%

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Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy

et al. 2017

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We have previously established that adipose tissue adjacent to breast tumors becomes inflamed by tumor-derived cytokines. This stimulates autotaxin (ATX) secretion from adipocytes, whereas breast cancer cells produce insignificant ATX. Lysophosphatidate produced by ATX promotes inflammatory cytokine secretion in a vicious inflammatory cycle, which increases tumor growth and metastasis and decreases response to chemotherapy. We hypothesized that damage to adipose tissue during radiotherapy for breast cancer should promote lysophosphatidic acid (LPA) signaling and further inflammatory signaling, which could potentially protect cancer cells from subsequent fractions of radiation therapy. To test this hypothesis, we exposed rat and human adipose tissue to radiation doses (0.25-5 Gy) that were expected during radiotherapy. This exposure increased mRNA levels for ATX, cyclooxygenase-2, IL-1β, IL-6, IL-10, TNF-α, and LPA and LPA receptors by 1.8- to 5.1-fold after 4 to 48 h. There were also 1.5- to 2.5-fold increases in the secretion of ATX and 14 inflammatory mediators after irradiating at 1 Gy. Inhibition of the radiation-induced activation of NF-κB, cyclooxygenase-2, poly (ADP-ribose) polymerase-1, or ataxia telangiectasia and Rad3-related protein blocked inflammatory responses to γ-radiation. Consequently, collateral damage to adipose tissue during radiotherapy could establish a comprehensive wound-healing response that involves increased signaling by LPA, cyclooxygenase-2, and other inflammatory mediators that could decrease the efficacy of further radiotherapy or chemotherapy.-Meng, G., Tang, X., Yang, Z., Benesch, M. G. K., Marshall, A., Murray, D., Hemmings, D. G., Wuest, F., McMullen, T. P. W., Brindley, D. N. Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy.

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Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy

et al. 2017

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“…Tamoxifen's effectiveness in the treatment of breast cancer is partly attributed to the apoptosis of tumor cells mediated by oxidative stress and increased ceramide intracellular level among other mechanisms . Tamoxifen also causes ceramide intracellular accumulation in neutrophils, therefore, we suspected that it could lead to neutrophilic apoptosis and concurrent improvement of airway inflammation.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of tamoxifen for the treatment of severe equine asthma

Mainguy-Seers

Picotte

Lavoie

2018

Veterinary Internal Medicne

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BackgroundTamoxifen, a selective estrogen receptor modulator, decreased airway neutrophilia and improved clinical signs in an experimental model of equine asthma, and induced neutrophilic apoptosis in vitro.Hypothesis/ObjectivesTamoxifen reduces airway neutrophilia and improves lung function in severe asthmatic horses.AnimalsTwelve severe asthmatic horses from a research herd.MethodsRandomized controlled blinded study design. The effects of a 12‐day oral treatment with tamoxifen (0.22 mg/kg, q24h) or dexamethasone (0.06 mg/kg, q24h) on lung function, endoscopic tracheal mucus score and bronchoalveolar lavage fluid cytology were compared.ResultsTamoxifen significantly improved the pulmonary resistance (R L; mean reduction of 1.15 cm H2O/L/s [CI: 0.29‐2.01, P = .007] on day 13), but had no effect on the other variables evaluated. Dexamethasone normalized lung function (mean reduction of R L of 2.48 cm H2O/L/s [CI: 1.54‐3.43, P < .0001] on day 13), without affecting airway neutrophilia.Conclusions and Clinical ImportanceResults of this study do not support the use of tamoxifen at the dose studied as an antineutrophilic medication in the treatment of asthmatic horses in chronic exacerbation.

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“…3 Tamoxifen is known to induce oxidative stress. 4 Therefore, we speculate that the effects of tamoxifen in their mouse model are due to an increased sensitivity to oxidative stress in mice with long-standing whole body Ncoa4 ablation. Our model of acute Ncoa4 ablation does not have baseline iron overload or a baseline alterations in erythropoiesis and while not formally tested, should not have a baseline increase in sensitivity to oxidative stress, thereby decreasing the possibility of an off-target issue with tamoxifen due to an induction of oxidative stress.…”

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“…Naiara Santana-Codina, 1 Sebastian Gableske, 1 Mark D. Fleming, 2 J. Wade Harper, 3 Alec C. Kimmelman 4 and Joseph D. Mancias 1…”

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The role of nuclear receptor co-activator 4 in erythropoiesis (Reply to Nai et al.)

et al. 2019

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We thank Nai and colleagues for their interest in our recently published paper, Santana-Codina et al., 1 and their comment, also published in Haematologica. 2 Their comment, containing new unpublished experimental data, questions the importance of nuclear receptor coactivator 4 (NCOA4) in acute erythropoietic expansion. Here, we respond to clarify inconsistencies in the interpretation of their new data with respect to our experiments and highlight the multiple lines of evidence that support our overall conclusions regarding the cell autonomous and non-autonomous roles of NCOA4 in supporting murine erythropoiesis. With respect to their concerns over the use of tamoxifen in our inducible model of acute whole body Ncoa4 genetic ablation: we stand by the conclusions of our experiments as they were tightly controlled with all appropriate genetic backgrounds and treatment controls utilized. While we agree that tamoxifen may have off-target effects on red blood cells (RBC), our experiments as designed and carried out were well-controlled. Specifically, mice in each group had no baseline alterations in systemic iron parameters or erythropoiesis prior to tamoxifen administration making the alterations observed most likely to be a result of acute Ncoa4 ablation leading to an acute loss of flux of ferritin through the autophagic degradation pathway thereby altering systemic iron homeostasis and basal erythropoiesis. The key difference in the new data presented by Nai and colleagues in their comment 2 is the presence of long-standing Ncoa4 knockout in their mouse model prior to administration of tamoxifen, which we argue makes their conclusions uninterpretable with respect to our data in an inducible knockout mouse model. Specifically, they use a mouse model with constitutive (from birth) total body knockout of Ncoa4, which is a distinct situation compared to acute ablation of Ncoa4 expression in an adult mice. The critical point here is that with a constitutive total body ablation of Ncoa4 from birth, erythropoiesis is altered in such a way that RBC at the time of tamoxifen administration already have accumulated long-standing significant changes that alter the baseline response to any agent that has potential deleterious effects on the RBC, such as tamoxifen. For that matter, Nai et al. do not present hemoglobin levels in wild-type mice that were subjected to gavage solely with the vehicle (corn oil) that was used to dissolve tamoxifen. Given that repeated gavage is expected to induce a profound stress response, it is unclear if the reduction in hemoglobin levels observed in wild type mice (and which form the basis of their arguments) can be attributed specifically to tamoxifen. While we cannot fully evaluate their claim regarding the lack of alterations in systemic iron parameters in the Sv129/J background they use given their reference to unpublished data, we do note that these Ncoa4 knockout animals appear to have altered baseline hematologic parameters with microcytosis and a trend towards decreased hemogolobin and he...

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Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance

Cited by 96 publications

References 81 publications

Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy

Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy

Efficacy of tamoxifen for the treatment of severe equine asthma

The role of nuclear receptor co-activator 4 in erythropoiesis (Reply to Nai et al.)

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