Integrative genome wide analysis of protein tyrosine phosphatases identifies CDC25C as prognostic and predictive marker for chemoresistance in breast cancer

Article type: Research Article

Authors: Topno, Rachel^{a; c; 1} | Nazam, Nazia^{b; 1} | Kumari, Pallawi^b | Kumar, Manoj^{a; d; *} | Agarwal, Pallavi^{b; *}

Affiliations: [a] Amity Food and Agriculture Foundation, Amity University Uttar Pradesh, Noida, India | [b] Amity Institute of Molecular Medicine and Stem Cell Research, Amity University Uttar Pradesh, Noida, India | [c] Institute of Human Genetics, CNRS – University of Montpellier, Montpellier, France | [d] Amity Institute of Genome Engineering, Amity University Uttar Pradesh, Noida, India

Correspondence: [*] Corresponding authors: Manoj Kumar, Amity Institute of Genome Engineering, Amity University Uttar Pradesh, Sector 125, Noida 201313, India. Tel.: +91 81306 06394. %****␣cbm-32-cbm200858_temp.tex␣Line␣125␣**** E-mail: mkumar18@amity. edu. Pallavi Agarwal, Amity Institute of Molecular Medicine and Stem Cell Research, Amity University Uttar Pradesh, Sector 125, Noida 201313, India. Tel.: +91 98712 88982; E-mail: [email protected].

Note: [1] Rachel Topno and Nazia Nazam contributed equally to this work.

Abstract: BACKGROUND: The breast cancer subtype deficient in estrogen receptor and human epidermal growth factor receptor-2 (ER-/HER2-) displays enhanced aggressiveness, metastasis and disease relapse due to chemoresistance. ER-/HER2- patients lack molecularly targeted treatment hence, new therapeutic and prognostic biomarkers are required for better patient management. OBJECTIVES: To investigate the prognostic role of protein tyrosine phosphatase genes in Breast Cancer and their relevance as predictive markers for chemoresistance. METHODS: We examined the expression of 114 protein tyrosine phosphatase (PTP) genes in 1700 breast cancer patient’s tumor samples with respect to ER-/HER2- subtype. Correlation of relevant candidates with chemoresistance was analyzed in breast cancer cells resistant to taxane/anthracycline based drugs. The prognostic value of key candidates was assessed using Kaplan Meier plots and Nottingham prognostic index and expression pattern was confirmed using qRT-PCR. The epigenetic regulation was analyzed using ChIP-Seq datasets. By plotting ROC plots, clinical outcome after treatment with taxane and anthracycline was established. RESULTS: Overexpression of CDC25A and CDC25C and under-expression of DUSP16 was observed in tumor samples of ER-/HER2- patients and breast cancer cells. Similar expression patterns of these candidate genes were observed in MCF7 cells resistant to paclitaxel and adriamycin and also correlated with poor prognosis of breast cancer patients. Increased CDC25A and CDC25C in ER-/HER2- cells was found to be regulated epigenetically by histone H3K4 methylation. Overall, the present study establishes increased expression of protein tyrosine phosphatase CDC25C as a poor prognostic marker for breast cancer. CONCLUSION: Our study highlights the role of CDC25C in chemoresistance to taxane and anthracycline based therapy and proposes CDC25C as a potential predictive marker for these cancer therapies.

Keywords: Breast cancer, chemoresistance, protein tyrosine phosphatase, ER-/HER2-, DUSP16, CDC25C

DOI: 10.3233/CBM-200858

Journal: Cancer Biomarkers, vol. 32, no. 4, pp. 491-504, 2021