High miR-30 Expression Associates with Improved Breast Cancer Patient Survival and Treatment Outcome

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Jamshidi, M.; Fagerholm, R.; Muranen, T.A.; Kaur, S.; Potdar, S.; Khan, S.; Netti, E.; Mpindi, J.-P.; Yadav, B.; Kiiski, J.I.; Aittomäki, K.; Heikkilä, P.; Saarela, J.; Bützow, R.; Blomqvist, C.; Nevanlinna, H. High miR-30 Expression Associates with Improved Breast Cancer Patient Survival and Treatment Outcome. Cancers 2021, 13, 2907.

Title: High miR-30 Expression Associates with Improved Breast Cancer Patient Survival and Treatment Outcome
Author: Jamshidi, Maral; Fagerholm, Rainer; Muranen, Taru A.; Kaur, Sippy; Potdar, Swapnil; Khan, Sofia; Netti, Eliisa; Mpindi, John-Patrick; Yadav, Bhagwan; Kiiski, Johanna I.; Aittomäki, Kristiina; Heikkilä, Päivi; Saarela, Jani; Bützow, Ralf; Blomqvist, Carl; Nevanlinna, Heli
Publisher: Multidisciplinary Digital Publishing Institute
Date: 2021-06-10
URI: http://hdl.handle.net/10138/330864
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 (<i>p</i><sub>BDDM</sub> = 0.035, HR = 0.63, 95% CI = 0.4–0.9) and breast cancer-specific survival (<i>p</i><sub>BCS </sub>= 0.018, HR = 0.61, 95% CI = 0.4–0.9), especially in HER2-positive (<i>p</i><sub>BDDM</sub> = 0.0009), ER-negative (<i>p</i><sub>BDDM </sub>= 0.003), p53-positive (<i>p</i><sub>BDDM </sub>= 0.011), and highly proliferating (<i>p</i><sub>BDDM </sub>= 0.0004) subgroups, and after adjuvant chemotherapy (<i>p</i><sub>BDDM </sub>= 0.035). MiR-30d predicted survival independently of standard prognostic markers (<i>p</i><sub>BDDM </sub>= 0.0004). In the drug-screening test, the miR-30 family sensitized the HER2-positive HCC1954 cell line to lapatinib (<i>p</i> &lt; 10<sup>–2</sup>) and HCC1937, MDA-MB-361, MDA-MB-436 and CAL120 to doxorubicin (<i>p</i> &lt; 10<sup>–4</sup>) 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.

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