Estrogen receptor-α directly regulates sensitivity to paclitaxel in neoadjuvant chemotherapy for breast cancer

Tokuda, Emi; Seino, Yutaka; Arakawa, Atsushi; Saito, Mitsue; Kasumi, Fujio; Hayashi, Shin Ichi; Yamaguchi, Yuri

doi:10.1007/s10549-011-1758-x

Cited by 31 publications

(27 citation statements)

References 28 publications

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“…We clearly observed that silencing the ERa in ERa positive breast cancer cells negated hyperglycaemia-induced chemoresistance; consistent with these findings we determined that exposing ERa negative breast cancer cells to different levels of glucose did not influence chemo-sensitivity. The ERa has been linked to chemoresistance previously: Tokuda et al (2012) showed that silencing the ERa in MCF7 breast cancer cells enhanced sensitivity to paclitaxel. This study was only performed under hyperglycaemic conditions and in that context their results were consistent with our findings.…”

Section: Discussionmentioning

confidence: 99%

Hyperglycaemia-induced chemoresistance in breast cancer cells: role of the estrogen receptor

Zeng¹,

Zielińska²,

Arshad³

et al. 2015

Endocrine-Related Cancer

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Breast cancer patients with diabetes respond less well to chemotherapy; in keeping with this we determined previously that hyperglycaemia-induced chemoresistance in estrogen receptor (ERa) positive breast cancer cells and showed that this was mediated by fatty acid synthase (FASN). More recent evidence suggests that the effect of metabolic syndrome and diabetes is not the same for all subtypes of breast cancer with inferior disease-free survival and worse overall survival only found in women with ERa positive breast cancer and not for other subtypes. Here we examined the impact of hyperglycaemia on ERa negative breast cancer cells and further investigated the mechanism underlying chemoresistance in ERa with a view to identifying strategies to alleviate hyperglycaemia-induced chemoresistance. We found that hyperglycaemia-induced chemoresistance was only observed in ERa breast cancer cells and was dependent upon the expression of ERa as chemoresistance was negated when the ERa was silenced. Hyperglycaemia-induced an increase in activation and nuclear localisation of the ERa that was downstream of FASN and dependent on the activation of MAPK. We found that fulvestrant successfully negated the hyperglycaemia-induced chemoresistance, whereas tamoxifen had no effect. In summary our data suggests that the ERa may be a predictive marker of poor response to chemotherapy in breast cancer patients with diabetes. It further indicates that anti-estrogens could be an effective adjuvant to chemotherapy in such patients and indicates the importance for the personalised management of breast cancer patients with diabetes highlighting the need for clinical trials of tailored chemotherapy for diabetic patients diagnosed with ERa positive breast cancers.

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Section: Discussionmentioning

confidence: 99%

Hyperglycaemia-induced chemoresistance in breast cancer cells: role of the estrogen receptor

Zeng¹,

Zielińska²,

Arshad³

et al. 2015

Endocrine-Related Cancer

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“…27 Other researchers have demonstrated that high ER expression affected estrogen-regulated genes and enhanced cell motility, which was associated with resistance to paclitaxel therapy. 28 …”

Section: Discussionmentioning

confidence: 99%

High Expression of Class III β-Tubulin Predicts Good Response to Neoadjuvant Taxane and Doxorubicin/Cyclophosphamide-Based Chemotherapy in Estrogen Receptor–Negative Breast Cancer

Wang¹,

Sparano²,

Fineberg³

et al. 2013

Clinical Breast Cancer

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Class III β-tubulin (βIII-tubulin) has been associated with tumor response to taxane-based therapies in breast cancer. However its role in the neoadjuvant setting has not been explored. We evaluated βIII-tubulin expression by immunohistochemistry in 44 patients, and found high expression associated with good pathologic response in estrogen receptor–negative (ER−) breast cancers. Our results give strong reason to consider βIII-tubulin as a predictive biomarker for neoadjuvant chemotherapy response. Background Expression of class III β–tubulin (βIII-tubulin) correlates with tumor progression and resistance to taxane-based therapies for several human malignancies including breast cancer. However its predictive value in a neoadjuvant setting in breast cancer remains unexplored. The objective of this explorative study was to determine whether βIII-tubulin expression in breast cancer correlated with pathologic characteristics and whether its expression was predictive of response to neoadjuvant chemotherapy. Patients and Methods We determined βIII-tubulin expression in 85 breast cancers, including 41 localized breast cancers treated with primary surgery and 44 treated with neoadjuvant chemotherapy before surgery. βIII-tubulin expression was evaluated by immunohistochemical methods and was correlated with pathologic characteristics and response to neoadjuvant chemotherapy using residual cancer burden (RCB) score. Results High βIII-tubulin expression was significantly associated with poorly differentiated high-grade breast cancers (P = .003) but not with tumor size, estrogen receptor (ER) status, or human epidermal growth factor receptor 2 (HER2)/neu overexpression. In ER− tumors treated with neoadjuvant chemotherapy, high βIII-tubulin expression was associated with a significantly greater likelihood of achieving a good pathologic response to chemotherapy as reflected by lower RCB scores (P = .021). Conclusion This study reveals differential βIII-tubulin expression in breast cancers of different histologic grades, hormone receptors, and HER2/neu status. It also suggests a potential role for βIII-tubulin as a predictive biomarker for response in neoadjuvant chemotherapy for ER− breast cancer, which has not been previously reported. These data provide a strong rationale for considering βIII-tubulin status and further validation of this marker in a large study.

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“…Chemotherapies and radiation therapy induce DNA damage, so ERα may suppress the DDR to reduce the efficacy of these treatments. Indeed, patients with ER positive breast cancers have significantly lower response rates to chemotherapy than those with ER negative cancers (88), and in vitro studies suggest this is dependent on ERα action (89–91). Co-administration of anti-estrogens and radiation therapy or chemotherapy appears to enhance therapy cytotoxicity and a likely explanation is that anti-estrogen treatment prevents pro-proliferative bypass of cytotoxicity by estrogen (66, 90).…”

Section: Perspectivesmentioning

confidence: 99%

Estrogen Signaling and the DNA Damage Response in Hormone Dependent Breast Cancers

2014

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Estrogen is necessary for the normal growth and development of breast tissue, but high levels of estrogen are a major risk factor for breast cancer. One mechanism by which estrogen could contribute to breast cancer is via the induction of DNA damage. This perspective discusses the mechanisms by which estrogen alters the DNA damage response (DDR) and DNA repair through the regulation of key effector proteins including ATM, ATR, CHK1, BRCA1, and p53 and the feedback on estrogen receptor signaling from these proteins. We put forward the hypothesis that estrogen receptor signaling converges to suppress effective DNA repair and apoptosis in favor of proliferation. This is important in hormone-dependent breast cancer as it will affect processing of estrogen-induced DNA damage, as well as other genotoxic insults. DDR and DNA repair proteins are frequently mutated or altered in estrogen responsive breast cancer, which will further change the processing of DNA damage. Finally, the action of estrogen signaling on DNA damage is also relevant to the therapeutic setting as the suppression of a DDR by estrogen has the potential to alter the response of cancers to anti-hormone treatment or chemotherapy that induces DNA damage.

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Estrogen receptor-α directly regulates sensitivity to paclitaxel in neoadjuvant chemotherapy for breast cancer

Cited by 31 publications

References 28 publications

Hyperglycaemia-induced chemoresistance in breast cancer cells: role of the estrogen receptor

Hyperglycaemia-induced chemoresistance in breast cancer cells: role of the estrogen receptor

High Expression of Class III β-Tubulin Predicts Good Response to Neoadjuvant Taxane and Doxorubicin/Cyclophosphamide-Based Chemotherapy in Estrogen Receptor–Negative Breast Cancer

Estrogen Signaling and the DNA Damage Response in Hormone Dependent Breast Cancers

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