Molecular signatures of neoadjuvant endocrine therapy for breast cancer: characteristics of response or intrinsic resistance

Harvell, Djuana M. E.; Spoelstra, Nicole S.; Singh, Meenakshi; McManaman, James L.; Finlayson, Christina; Phang, Tzu L.; Trapp, Susan; Hunter, Lawrence; Dye, Wendy W.; Borges, Virginia F.; Elias, Anthony; Horwitz, Kathryn B.; Richer, Jennifer K.

doi:10.1007/s10549-008-9897-4

Cited by 51 publications

(57 citation statements)

References 58 publications

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“…Changes in gene expression profiles in breast cancer tumours during endocrine treatment have been reported before (Kristensen et al, 2005;Mackay et al, 2007;Miller et al, 2007Miller et al, , 2009Harvell et al, 2008). To our knowledge this is the first study evaluating expression of nuclear receptor co-regulators in breast cancer patients during oestrogen deprivation.…”

Section: Discussionmentioning

confidence: 58%

Nuclear receptor co-activators and HER-2/neu are upregulated in breast cancer patients during neo-adjuvant treatment with aromatase inhibitors

et al. 2009

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BACKGROUND: Acquired resistance to endocrine therapy in breast cancer is poorly understood. Characterisation of the molecular response to aromatase inhibitors in breast cancer tissue may provide important information regarding development of oestrogen hypersensitivity. METHODS: We examined the expression levels of nuclear receptor co-regulators, the orphan nuclear receptor liver receptor homologue-1 and HER-2/neu growth factor receptor using real-time RT-PCR before and after 13 -16 weeks of primary medical treatment with the aromatase inhibitors anastrozole or letrozole. RESULTS: mRNA expression of the steroid receptor co-activator 1 (SRC-1) and peroxisome-proliferator-activated receptor g co-activator-1a (PGC-1a) was correlated (P ¼ 0.002), and both co-activators increased during treatment in the patient group as a whole (P ¼ 0.008 and P ¼ 0.032, respectively), as well as in the subgroup of patients achieving an objective treatment response (P ¼ 0.002 and P ¼ 0.006). Although we recorded no significant change in SRC-3/amplified in breast cancer 1 level, the expression correlated positively to the change of SRC-1 (P ¼ 0.002). Notably, we recorded an increase in HER-2/neu levels during therapy in the total patient group (18 out of 26; P ¼ 0.016), but in particular among responders (15 out of 21; P ¼ 0.008). CONCLUSION: Our results show an upregulation of co-activator mRNA and HER-2/neu during treatment with aromatase inhibitors. These mechanisms may represent an early adaption of the breast cancer cells to oestrogen deprivation in vivo.

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Section: Discussionmentioning

confidence: 58%

Nuclear receptor co-activators and HER-2/neu are upregulated in breast cancer patients during neo-adjuvant treatment with aromatase inhibitors

et al. 2009

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“…The study was fueled by previous observations that in ER-positive breast cancer responding to endocrine treatment, AR downregulation at the protein and mRNA level is observed, whereas no such effect is seen in nonresponsive tumors (56,57). In a cohort of 192 patients with earlystage ER-positive breast cancer receiving adjuvant tamoxifen treatment and another one of a randomized phase II trial assessing exemestane with or without tamoxifen, high AR:ER ratio was found to predict resistance to endocrine therapy in a statistically significant manner.…”

Section: Discussionmentioning

confidence: 99%

The Prognostic Role of Androgen Receptor in Patients with Early-Stage Breast Cancer: A Meta-analysis of Clinical and Gene Expression Data

Božović-Spasojević

Zardavas

Brohée

et al. 2017

Clinical Cancer Research

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Purpose: Androgen receptor (AR) expression has been observed in about 70% of patients with breast cancer, but its prognostic role remains uncertain.Experimental Design: To assess the prognostic role of AR expression in early-stage breast cancer, we performed a metaanalysis of studies that evaluated the impact of AR at the protein and gene expression level on disease-free survival (DFS) and/or overall survival (OS). Eligible studies were identified by systematic review of electronic databases using the MeSH-terms "breast neoplasm" and "androgen receptor" and were selected after a qualitative assessment based on the REMARK criteria. A pooled gene expression analysis of 35 publicly available microarray data sets was also performed from patients with early-stage breast cancer with available gene expression and clinical outcome data.Results: Twenty-two of 33 eligible studies for the clinical meta-analysis, including 10,004 patients, were considered as evaluable for the current study after the qualitative assessment. AR positivity defined by IHC was associated with improved DFS in all patients with breast cancer [multivariate (M) analysis, HR 0.46; 95% confidence interval (CI) 0.37-0.58, P < 0.001] and better OS [M-HR 0.53; 95% CI, 0.38-0.73, P < 0.001]. Thirty-five datasets including 7,220 patients were eligible for the pooled gene expression analysis. High AR mRNA levels were found to confer positive prognosis overall in terms of DFS (HR 0.82; 95% CI 0.72-0.92;P ¼ 0.0007) and OS (HR 0.84; 95% CI, 0.75-0.94; P ¼ 0.02) only in univariate analysis.Conclusions: Our analysis, conducted among more than 17,000 women with early-stage breast cancer included in clinical and gene expression analysis, demonstrates that AR positivity is associated with favorable clinical outcome. Clin Cancer Res; 23(11); 2702-12. Ó2016 AACR.

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“…AIs block the conversion of androgen to estrogen, thus increasing free testosterone and DHEA-S [70]. Previous studies have shown that patients with ER positive tumors that are responders to neoadjuvant AI therapy, display decreased AR mRNA and nuclear protein, while non-responders continue to have elevated AR expression [71, 72]. Our data are in accordance with previous reports that AR overexpression in breast cancer cell lines leads to tamoxifen and AI resistance [65, 73].…”

Section: Discussionmentioning

confidence: 99%

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer

Azariadis¹,

Kiagiadaki

Pelekanou³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Reports regarding the role of androgen in breast cancer (BC) are conflicting. Some studies suggest that androgen could lead to undesirable responses in the presence of certain BC tumor characteristics. We have shown that androgen induces C-X-C motif chemokine 12 (CXCL12) in BC cell lines. Our aim was to identify the mechanisms regulating the phenotypic effects of androgen-induced CXCL12 on Androgen Receptor (AR) positive BC cell lines. Methods: We analyzed the expression of CXCL12 and its receptors with qPCR and ELISA and the role of Nuclear Receptor Coactivator 1 (NCOA1) in this effect. AR effects on the CXCL12 promoter was studied via Chromatin-immunoprecipitation. We also analyzed publically available data from The Cancer Genome Atlas to verify AR-CXCL12 interactions and to identify the effect or Aromatase Inhibitors (AI) therapy on CXCL12 expression and disease progression in AR positive cases. Results: CXCL12 induction occurs only in AR-positive BC cell lines, possibly via an Androgen Response Element, upstream of the CXCL12 promoter. The steroid receptor co-regulator NCOA1 is critical for this effect. Androgen only induced the motility of p53-mutant BC cells T47D cells via upregulation of CXCR4 expression while they had no effect on wild-type p53 MCF-7 cells. Loss of CXCR4 expression and depletion of CXCL12 abolished the effect of androgen in T47D cells while inhibition of p53 expression in MCF-7 cells made them responsive to androgen and increased their motility in the presence to androgen. Patients with estrogen receptor positive (ER+)/AR+ BC treated with AIs were at increased risk of disease progression compared to ER+/AR+ non-AI treated and ER+/AR- AI treated cases. Conclusion: AIs may lead to unfavorable responses in some ER/AR positive BC cases, especially in patients with AR+, p53 mutant tumors.

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Molecular signatures of neoadjuvant endocrine therapy for breast cancer: characteristics of response or intrinsic resistance

Cited by 51 publications

References 58 publications

Nuclear receptor co-activators and HER-2/neu are upregulated in breast cancer patients during neo-adjuvant treatment with aromatase inhibitors

Nuclear receptor co-activators and HER-2/neu are upregulated in breast cancer patients during neo-adjuvant treatment with aromatase inhibitors

The Prognostic Role of Androgen Receptor in Patients with Early-Stage Breast Cancer: A Meta-analysis of Clinical and Gene Expression Data

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer

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