Identification of Protein Clusters Predictive of Response to Chemotherapy in Breast Cancer Patients

Department of Oncology & Haematology, University of Modena and Reggio Emilia, Modena, Italy.
Journal of Proteome Research (Impact Factor: 4.25). 10/2009; 8(11):4916-33. DOI: 10.1021/pr900239h
Source: PubMed


An attempt for the identification of potential biomarkers predictive of response to chemotherapy (CHT) in breast cancer patients has been performed by the use of two-dimensional electrophoresis and mass spectrometry analysis. Since growth and progression of tumor cells depend also on stromal factors in the microenvironment, we choose to investigate the proteins secreted in Tumor Interstitial Fluid (TIF) and in Normal Interstitial Fluids (NIF). One-hundred and twenty-two proteins have been analyzed and a comparison was also made between the proteomic profile of responders versus nonresponders to CHT. At baseline, proteins isolated in TIF and NIF of all the 28 patients show significant differences in expression. Two clusters of proteins, differentially expressed in TIF with respect to NIF were found. Most significant is the decreased expression in TIF of CRYAB. In the protein metabolism group, also FIBB was found decreased. Some proteins involved in energy pathways were overexpressed (PGAM-1, ALDO A, PGK1, G3Pcn), while some other were down-regulated (CAH2, G3Pdx, PRDX6, TPIS). The same trend was observed for signal transduction proteins, with 14-3-3-Z overexpressed, and ANXA2 and PEBP 1 down-regulated. Moreover, an analysis has been conducted comparing protein expression in interstitial fluids of responders and nonresponders, irrespective of TIF or NIF source. This analysis lead us to identify two clusters of proteins with a modified expression, which might be predictive of response to CHT. In responders, an increase in expression of LDHA, G3Pdx, PGK1sx (energy pathways), VIME (cell growth and maintenance) and 14-3-3-Z (signal transduction), coupled with a decreased expression of TPIS, CAH 2, G3Psx, PGK 1dx (energy pathways), TBB5 (cell growth and maintenance), LDHB and FIBB (protein metabolism), was found. We observed that CHT modifies the expression of these cluster proteins since, after treatment, their expression in TIF of responder is generally decreased. Patients not responding to CHT show an unchanged expression pattern in TIF, with the exception of protein 14-3-3-Z, which is overexpressed, and a decreased expression in NIF of several cluster proteins. In conclusion, the identification of protein clusters associated with response to CHT might be important for predicting the efficacy of a specific antineoplastic drug and for the development of less empiric strategies in choosing the therapy to be prescribed to the single patient.

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    • "In recent years, studies have reported that β-catenin can bind the TCF/LEF family of transcription factors, displacing a corepressor and changing them to activators of transcription[4]. LEF-1 is a key nuclear transcription factor in wnt/β-catenin signaling pathway,which abnormalities expression is associated with multiple tumors,such as osteosarcoma[13], breast cancer[14,15], colon cancer[16]and melanoma[17]etc. In a present study, PITX2 and LEF-1 have specific binding sites in the development of pituitary gland. "

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    • "ApoA1 was found in breast tumors, and its amount was correlated positively with chemotherapy resistance in malignant tumors [37]. In contrast, breast tumors later found responsive to chemotherapy secreted higher amount of apoA1 than tumors non-responsive to chemotherapy during short term ex vivo culture, while non-cancerous tissues secreted highest amount of apoA1 [38]. Furthermore, a successful reduction of breast cancer growth in mice by vitamin D treatment was accompanied by decrease of apoA1 production in tumor tissues [39]. "
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    ABSTRACT: Post-surgery therapies are given to early-stage breast cancer patients due to the possibility of residual micrometastasis, and optimized by clincopathological parameters such as tumor stage, and hormone receptor/lymph node status. However, current efficacy of post-surgery therapies is unsatisfactory, and may be varied according to unidentified patient genetic factors. Increases of breast cancer occurrence and recurrence have been associated with dyslipidemia, which can attribute to other known risk factors of breast cancer including obesity, diabetes and metabolic syndrome. Thus we reasoned that dyslipidemia-associated nucleotide polymorphisms (SNPs) on the APOA1/C3/A5 gene cluster may predict breast cancer risk and tumor progression. We analyzed the distribution of 5 selected APOA1/C3/A5 SNPs in recruited Taiwanese breast cancer patients (n=223) and healthy controls (n=162). The association of SNP (APOA1 rs670) showing correlation with breast cancer with baseline and follow-up parameters was further examined. APOA1 rs670 A allele carriage was higher in breast cancer patients than controls (59.64% vs. 48.77%, p=0.038). The rs670 A allele carrying patients showed less favorable baseline phenotype with positive lymph nodes (G/A: OR=3.32, 95%CI=1.77-6.20, p<0.001; A/A: OR=2.58, 95%CI=1.05-6.32, p=0.039) and negative hormone receptor expression (A/A: OR=4.85, 95%CI=1.83-12.83, p=0.001) in comparison to G/G carriers. Moreover, rs670 A/A carrying patients had higher risks in both tumor recurrence (HR=3.12, 95%CI=1.29-7.56, p=0.012) and mortality (HR=4.36, 95%CI=1.52-12.47, p=0.006) than patients with no A alleles after adjustments for associated baseline parameters. Furthermore, the prognostic effect of rs670 A/A carriage was most evident in lymph node-negative patients, conferring to the highest risks of recurrence (HR=4.98, 95%CI=1.40-17.70, p=0.013) and mortality (HR=9.87, 95%CI=1.60-60.81, p=0.014) than patients with no A alleles. APOA1 rs670 A/A carriage showed poor post-surgery prognosis in Taiwanese lymph node-negative breast cancer patients, whose prognosis were considered better and adjuvant treatment might be less stringent according to currently available assessment protocols. Our findings suggest that APOA1 rs670 indicate a post-surgery risk of breast cancer disease progression, and that carriers of this SNP may benefit from more advanced disease monitoring and therapy regimens than the current regular standards. Furthermore, control of lipid homeostasis might protect APOA1 rs670 minor allele carriers from breast cancer occurrence and progression.
    Full-text · Article · Jul 2013 · BMC Cancer
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    • "Genes, which were significantly associated with the pathway networks in IPA were searched in the literature for their roles in breast cancer and are compiled along with relevant references in Table  5 for upregulated genes and in Table  6 for downregulated genes. A total of 27 upregulated (ACHE [11], HSPA1L [12], NES [13], P2RY2 [14], PLCG1 [15], PPARGC1A [16], PRKCQ [17], SNTA1 [18], ALDOA [19], GNAO1 [20], SLC16A3 [21], TPI1 [22], ELL2 [23], CCNG1 [24], E2F6 [25], ESRRG [26], MAPK12 [27], HSD17B7 [28], TACC2 [29], DDX1 [30], MYH1 [31], UCP1 [32], PACSIN3 [33], PGM1 [34], TLN2 [35], ADIPOR1 [36], PITX1 [37]) and 8 downregulated genes (CELSR2 [38], PRKCB [39], KIT [40], MAP2 [41], TDGF1 [42], ELF1 [43], RUNX1 [44], TYMS [45]) showed association with breast cancer. Furthermore, the data files with the complete list of the upregulated and downregulated networks are presented in Additional files 3 and 4, respectively, for further reference. "
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    ABSTRACT: Background Breast tissue is among the most sensitive tissues to the carcinogenic actions of ionizing radiation and epidemiological studies have linked radiation exposure to breast cancer. Currently, molecular understanding of radiation carcinogenesis in mammary gland is hindered due to the scarcity of in vivo long-term follow up data. We undertook this study to delineate radiation-induced persistent alterations in gene expression in mouse mammary glands 2-month after radiation exposure. Methods Six to eight week old female C57BL/6J mice were exposed to 2 Gy of whole body γ radiation and mammary glands were surgically removed 2-month after radiation. RNA was isolated and microarray hybridization performed for gene expression analysis. Ingenuity Pathway Analysis (IPA) was used for biological interpretation of microarray data. Real time quantitative PCR was performed on selected genes to confirm the microarray data. Results Compared to untreated controls, the mRNA levels of a total of 737 genes were significantly (p<0.05) perturbed above 2-fold of control. More genes (493 genes; 67%) were upregulated than the number of downregulated genes (244 genes; 33%). Functional analysis of the upregulated genes mapped to cell proliferation and cancer related canonical pathways such as ‘ERK/MAPK signaling’, ‘CDK5 signaling’, and ‘14-3-3-mediated signaling’. We also observed upregulation of breast cancer related canonical pathways such as ‘breast cancer regulation by Stathmin1’, and ‘HER-2 signaling in breast cancer’ in IPA. Interestingly, the downregulated genes mapped to fewer canonical pathways involved in cell proliferation. We also observed that a number of genes with tumor suppressor function (GPRC5A, ELF1, NAB2, Sema4D, ACPP, MAP2, RUNX1) persistently remained downregulated in response to radiation exposure. Results from qRT-PCR on five selected differentially expressed genes confirmed microarray data. The PCR data on PPP4c, ELF1, MAPK12, PLCG1, and E2F6 showed similar trend in up and downregulation as has been observed with the microarray. Conclusions Exposure to a clinically relevant radiation dose led to long-term activation of mammary gland genes involved in proliferative and metabolic pathways, which are known to have roles in carcinogenesis. When considered along with downregulation of a number of tumor suppressor genes, our study has implications for breast cancer initiation and progression after therapeutic radiation exposure.
    Full-text · Article · Dec 2012 · Radiation Oncology
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