Chemotherapy-induced tumor gene expression changes in human breast cancers

Lee, Soo‐Chin; Xu, Xin; Lim, Yi-Wan; Iau, Philip; Sukri, Norita; Lim, Siak Piang; Yap, Hui Ling; Yeo, Wee Song; Tan, Patrick; Tan, S. G.; McLeod, Howard L.; Goh, Boon-Cher

doi:10.1097/fpc.0b013e32831ebb5d

Cited by 33 publications

(34 citation statements)

References 25 publications

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“…In this way, AC contributes to tumor cell survival by depleting ceramide levels while increasing the levels of S1-P. Aberrant AC expression has been reported in tumors of the prostate [13,29], breast [8,14,30], head and neck [31,32], and melanoma [33]. Furthermore, tumor associated AC expression has been shown to be induced by chemotherapy [19,34] and radiation [35]. Other studies suggest that tumor AC expression may be a predictor of response to neoadjuvant breast cancer therapies [36,37], and a prognostic indicator in melanoma [33].…”

Section: Introductionmentioning

confidence: 96%

C6-Ceramide and targeted inhibition of acid ceramidase induce synergistic decreases in breast cancer cell growth

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Fabriás

Delgado

et al. 2011

Breast Cancer Res Treat

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The sphingolipid ceramide is known to play a central role in chemo- and radiation-induced cell death. Acid ceramidase (AC) hydrolyzes ceramide, and thus reduces intracellular levels of this proapoptotic lipid. The role of AC as a putative anticancer target is supported by reports of upregulation in prostate cancer and in some breast tumors. In this study, we determined whether the introduction of an AC inhibitor would enhance the apoptosis-inducing effects of C6-ceramide (C6-cer) in breast cancer cells. Cultured breast cancer cells were treated with DM102 [(2R,3Z)-N-(1-hydroxyoctadec-3-en-2-yl)pivalamide, C6-cer, or the combination. Cell viability and cytotoxic synergy were assessed. Activation of apoptotic pathways, generation of reactive oxygen species, and mitochondrial transmembrane potential were determined. DM102 was a more effective AC inhibitor than N-oleoylethanolamine (NOE) and (1R,2R)-2-N-(tetradecanoylamino)-1-(4'-nitrophenyl)-1,3-propandiol (B-13) in MDA-MB-231, MCF-7, and BT-474 cells. As single agents, C6-cer (IC(50) 5-10 μM) and DM102 (IC(50) 20 μM) were only moderately cytotoxic in MDA-MB-231, MCF-7, and SK-BR-3 cells. Co-administration, however, produced synergistic decreases in viability (combination index <0.5) in all cell lines. Apoptosis was confirmed in MDA-MB-231 cells by detection of caspase 3 cleavage and a >3-fold increase in caspase 3/7 activation, PARP cleavage, and a >70% increase in Annexin-V positive cells. C6-cer/DM102 increased ROS levels 4-fold in MDA-MB-231 cells, shifted the ratio of Bax:Bcl-2 to >9-fold that of control cells, and resulted in mitochondrial membrane depolarization. DM102 also increased the synthesis of (3)H-palmitate-labeled long-chain ceramides by 2-fold when C6-cer was present. These data support the effectiveness of targeting AC in combination with exogenous short-chain ceramide as an anticancer strategy, and warrant continued investigation into the utility of the C6-cer/DM102 drug duo in human breast cancer.

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Section: Introductionmentioning

confidence: 96%

C6-Ceramide and targeted inhibition of acid ceramidase induce synergistic decreases in breast cancer cell growth

Flowers

Fabriás

Delgado

et al. 2011

Breast Cancer Res Treat

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“…It is of considerable importance to elucidate genetic changes and to identify prognostic biomarkers associated with NCT, which can provide a more accurate assessment of individual treatment. The altered gene expression profiles of breast cancer under NCT have been described (2)(3)(4). However, to the best of our knowledge, a comparison of the exomes and genomes of pre-and post-NCT samples does not yet exist.…”

Section: Introductionmentioning

confidence: 99%

Favorable Prognostic Impact in Loss of TP53 and PIK3CA Mutations after Neoadjuvant Chemotherapy in Breast Cancer

Jiang

Bao

et al. 2014

Cancer Research

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We investigated the loss of somatic mutations in TP53 and PIK3CA in breast cancer tissue after neoadjuvant chemotherapy (NCT) and the clinical relevance of the observed mutation profiles. Samples were derived from three cohorts: Cohort 1 consisting of 206 patients undergoing NCT with matched pre-and postchemotherapy tumor tissues; Cohort 2 consisting of 158 additional patients undergoing NCT; and Cohort 3, consisting of 81 patients undergoing chemotherapy with prechemotherapy tumor tissues. In the first cohort, somatic mutations in TP53 or PIK3CA were identified in 24.8% of the pre-NCT tumor samples but in only 12.1% of the post-NCT tumor samples (P < 0.001). Patients with initial TP53 and PIK3CA mutations who became negative for the mutations after NCT had a higher Miller-Payne score (P ¼ 0.008), improved disease-free survival, and improved overall survival than those with no change or the opposite change. The association of loss of mutations in TP53 and PIK3CA and improved survival was successfully validated in the second cohort. In addition, 28.4% of the tumors showed intratumoral heterogeneity of somatic mutations in TP53 or PIK3CA, whereas 71.6% were homogeneous, either with or without the mutations. Our data reveal the novel concept that chemotherapy may reduce mutation frequency in patients with breast cancer. Furthermore, the loss of somatic mutations in TP53 and PIK3CA may be translated to biomarkers for prognosis via further verification, which may optimize the choice of sequential therapy and improve patient survival. Cancer Res; 74(13); 3399-407. Ó2014 AACR.

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“…Although NCT is effective in reducing the size of the primary tumour before surgery, residual disease after NCT is common and is associated with a higher risk of metastatic recurrence compared with patients achieving pathologic complete remission 12 . The altered gene-expression profiles of breast cancer under NCT have been described [13][14][15] . Recent studies using nextgeneration sequencing to analyse residual breast cancer after NCT identified diverse pathway activation in drug-resistant tumour cells 16 .…”

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confidence: 99%

Enriched variations in TEKT4 and breast cancer resistance to paclitaxel

Jiang

Peng

et al. 2014

Nat Commun

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Among chemotherapeutic agents, paclitaxel has shown great efficacy against breast cancer. Prediction of paclitaxel response may improve patient outcomes. Here we show, using exome sequencing, that in comparison with pre-treatment biopsies, two TEKT4 germline variations are enriched in post-treatment tumours. We find TEKT4 variations in B10% of an independent cohort of 84 pairs of samples. Tektin4 (encoded by TEKT4) associates closely with tubulin in doublet microtubules and helps stabilize these structures. These two TEKT4 germline variations in a high cis linkage are biologically relevant, as the ectopic expression of variant TEKT4 deregulates the microtubule stability, antagonizes the paclitaxel-induced stabilizing effect of microtubules and increases paclitaxel resistance. Furthermore, TEKT4 germline variations are associated with reduced disease-free survival and overall survival compared with wild-type TEKT4 in patients undergoing paclitaxel-based chemotherapy. Taken together, we reveal a potential mechanism of resistance to paclitaxel through the acquisition of germline variations in breast cancer.

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Chemotherapy-induced tumor gene expression changes in human breast cancers

Cited by 33 publications

References 25 publications

C6-Ceramide and targeted inhibition of acid ceramidase induce synergistic decreases in breast cancer cell growth

C6-Ceramide and targeted inhibition of acid ceramidase induce synergistic decreases in breast cancer cell growth

Favorable Prognostic Impact in Loss of TP53 and PIK3CA Mutations after Neoadjuvant Chemotherapy in Breast Cancer

Enriched variations in TEKT4 and breast cancer resistance to paclitaxel

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