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Clinical proteomics of invasive breast carcinoma reveals a major role for proline metabolism in imparting drug resistance

ABSTRACT: Aggressive breast tumors are routinely treated with pre-operative chemotherapy. However, a subset of patients have recurrence despite adjuvant treatment. To identify metabolic processes involved in drug resistance, we took a mass spectrometry-based proteomic approach, and analyzed a breast cancer cohort of 113 samples comprising of breast tumors before and after chemotherapy, with matched tumor adjacent normal tissue from partial responders that underwent neoadjuvant treatment (NAT). Pattern analysis of 7180 proteins revealed more than 1000 proteins with significantly differential expression in primary tumor relative to the healthy tissue, which do not respond to treatment, in treatment resistant patients. Among those, we found significant upregulation of the proline biosynthesis pathway, primarily, PYCR1 that significantly correlated with lower recurrence free survival time in our cohort. Functional analysis showed that PYCR1 induced a pro-survival effect upon treatment with chemotherapy drugs thus emphasizing the potential role of PYCR1 in drug resistance in advanced breast cancer.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast Invasive Ductal Carcinoma Cell

DISEASE(S): Breast Cancer

SUBMITTER: Tamar Geiger

LAB HEAD: Tamar Geiger

PROVIDER: PXD012000 | Pride | 2020-08-24

REPOSITORIES: Pride

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Project description:Introduction: MicroRNAs (miRNAs) are small non-coding RNA that play a vital role in cancer progression. Neo-adjuvant chemotherapy (NAC) has become the standard of care for locally advanced breast cancer. The aim of this study was to evaluate miRNA alterations during NAC using multiple samples of tissue and serum to correlate miRNA expression with clinico-pathological features and patient outcomes. Methods: Tissue and serum samples were collected from patients with locally advanced breast cancer undergoing NAC at four time points: time of diagnosis, after the first and fourth cycle of doxorubicin/cyclophosphamide treatment, and after the fourth cycle of docetaxel administration. First, we evaluated the miRNA expression profiles in tissue and correlated expression with clinico-pathological features. Then, a panel of four miRNAs (miR-451, miR-3200, miR-21, and miR-205) in serum samples was further validated using quantitative reverse-transcription polymerase chain reaction (RT-qPCR). The alterations in serum levels of miRNA, associations with clinical and pathological responses, correlation with clinico-pathological features, and survival outcomes were studied using Friedman, Mann-Whitney U, Spearman, Wilcoxon signed-ranks tests. Pâ¤0.05 was considered statistically significant. Results: We analyzed 32 tissue samples and 108 serum samples from 8 patients and 27 patients, respectively. MicroRNA expression profiling of tumor versus normal tissue revealed more than 100 differentially expressed miRNAs. Serum miR-451 levels were significantly decreased during treatment, and higher serum levels were associated with improved clinical and pathological responses and disease-free survival. The serum levels of miR-3200 declined during NAC, and higher serum levels were associated with lower residual breast cancer burden and relapse rates. Conclusion: Variations in serum miRNA levels during NAC treatment may be therapeutically significant for predicting response and survival outcomes. Serum and tissue from a total of 27 consecutive patients diagnosed with locally advanced breast cancer undergoing NAC treatment were collected however microarray data were generated from tissue biopsy of 5 patients at four timepoints for both Normal and tumor. Additionally 3 tissue from only tumor at four timepoints and 6 patients at two timepoint T1 and T4

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Clinical proteomics of invasive breast carcinoma reveals a major role for proline metabolism in imparting drug resistance

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