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

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

doi:10.3390/cancers13122907

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

Cancers (Basel). 2021 Jun 10;13(12):2907. doi: 10.3390/cancers13122907.

Authors

Maral Jamshidi¹, Rainer Fagerholm¹, Taru A Muranen¹, Sippy Kaur^{1

2}, Swapnil Potdar³, Sofia Khan^{1

4}, Eliisa Netti¹, John-Patrick Mpindi³, Bhagwan Yadav³, Johanna I Kiiski¹, Kristiina Aittomäki^{5

6}, Päivi Heikkilä^{2

7}, Jani Saarela³, Ralf Bützow^{1

2}, Carl Blomqvist⁸, Heli Nevanlinna¹

Affiliations

¹ Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, 00029 Helsinki, Finland.
² Department of Pathology, University of Helsinki and Helsinki University Hospital, 00029 Helsinki, Finland.
³ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014 Helsinki, Finland.
⁴ Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
⁵ Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, 00029 Helsinki, Finland.
⁶ Department of Clinical Genetics, HUS Diagnostic Center, HUSLAB, 00029 Helsinki, Finland.
⁷ Department of Pathology, HUS Diagnostic Center, HUSLAB, 00029 Helsinki, Finland.
⁸ Department of Oncology, University of Helsinki and Helsinki University Hospital, 00029 Helsinki, Finland.

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 (p_BDDM = 0.035, HR = 0.63, 95% CI = 0.4-0.9) and breast cancer-specific survival (p_BCS = 0.018, HR = 0.61, 95% CI = 0.4-0.9), especially in HER2-positive (p_BDDM = 0.0009), ER-negative (p_BDDM = 0.003), p53-positive (p_BDDM = 0.011), and highly proliferating (p_BDDM = 0.0004) subgroups, and after adjuvant chemotherapy (p_BDDM = 0.035). MiR-30d predicted survival independently of standard prognostic markers (p_BDDM = 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.

Keywords: HER-2; anthracycline; breast cancer; chemotherapy; doxorubicin; lapatinib; metastasis; miR-30; p53; survival.

Abstract

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