1. High miR-30 Expression Associates with Improved Breast Cancer Patient Survival and Treatment Outcome
- Author
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Maral Jamshidi, Rainer Fagerholm, Taru A. Muranen, Sippy Kaur, Swapnil Potdar, Sofia Khan, Eliisa Netti, John-Patrick Mpindi, Bhagwan Yadav, Johanna I. Kiiski, Kristiina Aittomäki, Päivi Heikkilä, Jani Saarela, Ralf Bützow, Carl Blomqvist, Heli Nevanlinna, University of Helsinki, HUS Gynecology and Obstetrics, University of Helsinki, Faculty Common Matters, University of Helsinki, Institute for Molecular Medicine Finland, University of Helsinki, Helsinki Institute of Life Science HiLIFE, University of Helsinki, INDIVIDRUG - Individualized Drug Therapy, University of Helsinki, Medicum, University of Helsinki, HUSLAB, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Helsinki University Hospital Area, Faculty Common Matters (Faculty of Biology and Environmental Sciences), Clinicum, Medicum, Department of Pathology, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, INDIVIDRUG - Individualized Drug Therapy, Research Programs Unit, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, HUS Diagnostic Center, HUS Comprehensive Cancer Center, and Department of Oncology
- Subjects
p53 ,PROTEIN EXPRESSION ,MICRORNAS ,education ,INVASION ,3122 Cancers ,SUPPRESS ,chemotherapy ,anthracycline ,survival ,doxorubicin ,Article ,PROGNOSTIC-FACTORS ,breast cancer ,3123 Gynaecology and paediatrics ,metastasis ,miR-30 ,BRCA2 MUTATIONS ,lapatinib ,skin and connective tissue diseases ,RC254-282 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,EPITHELIAL-MESENCHYMAL TRANSITION ,HER-2 ,HYBRIDIZATION ,RESISTANCE - Abstract
Deregulated miRNA expression has been suggested in several stages of breast cancer pathogenesis. We have studied the miR-30 family, in particular miR-30d, in relation to breast cancer patient survival and treatment outcomes. With tumor specimens from 1238 breast cancer patients, we analyzed the association of miR-30d expression with tumor characteristics with the 5-year occurrence of breast cancer-specific death or distant metastasis (BDDM), and with 10-year breast cancer survival (BCS). We conducted a two-stage drug-screen to investigate the impact of miR-30 family members (miR-30a-30e) on sensitivity to doxorubicin and lapatinib in six breast cancer cell lines HCC1937, HCC1954, MDA-MB-361, MCF7, MDA-MB-436 and CAL-120, using drug sensitivity scores (DSS) to compare the miR-30 family mimics to their specific inhibitors. The study was complemented with Ingenuity Pathway Analysis (IPA) with the METABRIC data. We found that while high miR-30d expression is typical for aggressive tumors, it predicts better metastasis-free (pBDDM = 0.035, HR = 0.63, 95% CI = 0.4–0.9) and breast cancer-specific survival (pBCS = 0.018, HR = 0.61, 95% CI = 0.4–0.9), especially in HER2-positive (pBDDM = 0.0009), ER-negative (pBDDM = 0.003), p53-positive (pBDDM = 0.011), and highly proliferating (pBDDM = 0.0004) subgroups, and after adjuvant chemotherapy (pBDDM = 0.035). MiR-30d predicted survival independently of standard prognostic markers (pBDDM = 0.0004). In the drug-screening test, the miR-30 family sensitized the HER2-positive HCC1954 cell line to lapatinib (p <, 10−2) and HCC1937, MDA-MB-361, MDA-MB-436 and CAL120 to doxorubicin (p <, 10−4) with an opposite impact on MCF7. According to the pathway analysis, the miR-30 family has a suppressive effect on cell motility and metastasis in breast cancer. Our results suggest prognostic and predictive potential for the miR-30 family, which warrants further investigation.
- Published
- 2021