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Increased levels of choline metabolites are an early marker of docetaxel treatment response in BRCA1-mutated mouse mammary tumors: an assessment by ex vivo proton magnetic resonance spectroscopy.

van Asten JJ, Vettukattil R, Buckle T, Rottenberg S, van Leeuwen F, Bathen TF, Heerschap A - J Transl Med (2015)

Bottom Line: The HRMAS spectra revealed significant metabolic differences between sensitive and resistant tissue samples.Shortly after treatment (1-2 days) the normalized choline metabolite levels were significantly increased by more than 30% in the sensitive group coinciding with the time of highest apoptotic activity induced by docetaxel.Thus both pre- and post-treatment tissue levels of choline compounds have potential to predict response to docetaxel treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. Sjaak.vanAsten@radboudumc.nl.

ABSTRACT

Background: Docetaxel is one of the most frequently used drugs to treat breast cancer. However, resistance or incomplete response to docetaxel is a major challenge. The aim of this study was to utilize MR metabolomics to identify potential biomarkers of docetaxel resistance in a mouse model for BRCA1-mutated breast cancer.

Methodology: High resolution magic angle spinning (HRMAS) (1)H MR spectroscopy was performed on tissue samples obtained from docetaxel-sensitive or -resistant BRCA1-mutated mammary tumors in mice. Measurements were performed on samples obtained before treatment and at 1-2, 3-5 and 6-7 days after a 25 mg/kg dose of docetaxel. The MR spectra were analyzed by multivariate analysis, followed by analysis of the signals of individual compounds by peak fitting and integration with normalization to the integral of the creatine signal and of all signals between 2.9 and 3.6 ppm.

Results: The HRMAS spectra revealed significant metabolic differences between sensitive and resistant tissue samples. In particular choline metabolites were higher in resistant tumors by more than 50% with respect to creatine and by more than 30% with respect to all signals between 2.9 and 3.6 ppm. Shortly after treatment (1-2 days) the normalized choline metabolite levels were significantly increased by more than 30% in the sensitive group coinciding with the time of highest apoptotic activity induced by docetaxel. Thereafter, choline metabolites in these tumors returned towards pre-treatment levels. No change in choline compounds was observed in the resistant tumors over the whole time of investigation.

Conclusions: Relative tissue concentrations of choline compounds are higher in docetaxel resistant than in sensitive BRCA1-mutated mouse mammary tumors, but in the first days after docetaxel treatment only in the sensitive tumors an increase of these compounds is observed. Thus both pre- and post-treatment tissue levels of choline compounds have potential to predict response to docetaxel treatment.

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1H HRMAS spectra and Principal Component Analysis (PCA) of control tumor samples. A: The mean spectra of resistant tumor (red) show increased choline compounds compared to those of sensitive tumors (blue). B: Biplot [42] showing PCA analysis of HRMAS spectra. Docetaxel sensitive samples are shown with black triangle and resistant samples with squares. Arrows are drawn based on the loading plots to show the important metabolites responsible for the demarcation between the groups. Resistant samples have higher levels of GPC, PCho and Choline.
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Fig1: 1H HRMAS spectra and Principal Component Analysis (PCA) of control tumor samples. A: The mean spectra of resistant tumor (red) show increased choline compounds compared to those of sensitive tumors (blue). B: Biplot [42] showing PCA analysis of HRMAS spectra. Docetaxel sensitive samples are shown with black triangle and resistant samples with squares. Arrows are drawn based on the loading plots to show the important metabolites responsible for the demarcation between the groups. Resistant samples have higher levels of GPC, PCho and Choline.

Mentions: A comparison of spectra obtained by 1H HRMAS MRS of resistant and sensitive breast cancer tissue shows some clear spectral differences between 3.1 and 3.4 ppm (Figure 1A). Analysis by PCA of spectra obtained before the start of treatment (day 0), revealed that the tumors indeed were metabolically distinct (Figure 1B). All choline groups including phosphocholines (PCho), free choline (Cho) and glycerophosphocholines (GPC) were higher in resistant than in sensitive tumors. In contrast, PCA indicated that sensitive control tumors had higher levels of glycine (Gly), taurine (Tau) and Cr. For other metabolites with signals in the spectral region between 2.9 and 4.5 ppm, such as myo-inositol and ethanolamine, no differences could be detected between the two tumor lines.Figure 1


Increased levels of choline metabolites are an early marker of docetaxel treatment response in BRCA1-mutated mouse mammary tumors: an assessment by ex vivo proton magnetic resonance spectroscopy.

van Asten JJ, Vettukattil R, Buckle T, Rottenberg S, van Leeuwen F, Bathen TF, Heerschap A - J Transl Med (2015)

1H HRMAS spectra and Principal Component Analysis (PCA) of control tumor samples. A: The mean spectra of resistant tumor (red) show increased choline compounds compared to those of sensitive tumors (blue). B: Biplot [42] showing PCA analysis of HRMAS spectra. Docetaxel sensitive samples are shown with black triangle and resistant samples with squares. Arrows are drawn based on the loading plots to show the important metabolites responsible for the demarcation between the groups. Resistant samples have higher levels of GPC, PCho and Choline.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4404119&req=5

Fig1: 1H HRMAS spectra and Principal Component Analysis (PCA) of control tumor samples. A: The mean spectra of resistant tumor (red) show increased choline compounds compared to those of sensitive tumors (blue). B: Biplot [42] showing PCA analysis of HRMAS spectra. Docetaxel sensitive samples are shown with black triangle and resistant samples with squares. Arrows are drawn based on the loading plots to show the important metabolites responsible for the demarcation between the groups. Resistant samples have higher levels of GPC, PCho and Choline.
Mentions: A comparison of spectra obtained by 1H HRMAS MRS of resistant and sensitive breast cancer tissue shows some clear spectral differences between 3.1 and 3.4 ppm (Figure 1A). Analysis by PCA of spectra obtained before the start of treatment (day 0), revealed that the tumors indeed were metabolically distinct (Figure 1B). All choline groups including phosphocholines (PCho), free choline (Cho) and glycerophosphocholines (GPC) were higher in resistant than in sensitive tumors. In contrast, PCA indicated that sensitive control tumors had higher levels of glycine (Gly), taurine (Tau) and Cr. For other metabolites with signals in the spectral region between 2.9 and 4.5 ppm, such as myo-inositol and ethanolamine, no differences could be detected between the two tumor lines.Figure 1

Bottom Line: The HRMAS spectra revealed significant metabolic differences between sensitive and resistant tissue samples.Shortly after treatment (1-2 days) the normalized choline metabolite levels were significantly increased by more than 30% in the sensitive group coinciding with the time of highest apoptotic activity induced by docetaxel.Thus both pre- and post-treatment tissue levels of choline compounds have potential to predict response to docetaxel treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. Sjaak.vanAsten@radboudumc.nl.

ABSTRACT

Background: Docetaxel is one of the most frequently used drugs to treat breast cancer. However, resistance or incomplete response to docetaxel is a major challenge. The aim of this study was to utilize MR metabolomics to identify potential biomarkers of docetaxel resistance in a mouse model for BRCA1-mutated breast cancer.

Methodology: High resolution magic angle spinning (HRMAS) (1)H MR spectroscopy was performed on tissue samples obtained from docetaxel-sensitive or -resistant BRCA1-mutated mammary tumors in mice. Measurements were performed on samples obtained before treatment and at 1-2, 3-5 and 6-7 days after a 25 mg/kg dose of docetaxel. The MR spectra were analyzed by multivariate analysis, followed by analysis of the signals of individual compounds by peak fitting and integration with normalization to the integral of the creatine signal and of all signals between 2.9 and 3.6 ppm.

Results: The HRMAS spectra revealed significant metabolic differences between sensitive and resistant tissue samples. In particular choline metabolites were higher in resistant tumors by more than 50% with respect to creatine and by more than 30% with respect to all signals between 2.9 and 3.6 ppm. Shortly after treatment (1-2 days) the normalized choline metabolite levels were significantly increased by more than 30% in the sensitive group coinciding with the time of highest apoptotic activity induced by docetaxel. Thereafter, choline metabolites in these tumors returned towards pre-treatment levels. No change in choline compounds was observed in the resistant tumors over the whole time of investigation.

Conclusions: Relative tissue concentrations of choline compounds are higher in docetaxel resistant than in sensitive BRCA1-mutated mouse mammary tumors, but in the first days after docetaxel treatment only in the sensitive tumors an increase of these compounds is observed. Thus both pre- and post-treatment tissue levels of choline compounds have potential to predict response to docetaxel treatment.

Show MeSH
Related in: MedlinePlus