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Four miRNAs associated with aggressiveness of lymph node-negative, estrogen receptor-positive human breast cancer.

ABSTRACT: In this study, we quantified 249 mature micro-RNA (miRNA) transcripts in estrogen receptor-positive (ER(+)) primary breast tumors of patients with lymph node-negative (LNN) disease to identify miRNAs associated with metastatic capability. In addition, the prognostic value of the candidate miRNAs was determined in ER(-)/LNN breast cancer. Unsupervised analysis in a prescreening set of 38 patients identified three subgroups predominantly driven by three miRNA signatures: an ER-driven luminal B-associated miRNA signature, a stromal miRNA signature, and an overexpressed miRNA cluster located on chromosome 19q23, but these intrinsic miRNA signatures were not associated with tumor aggressiveness. Supervised analysis in the initial subset and subsequent analysis in additional tumors significantly linked four miRNAs (miR-7, miR-128a, miR-210, and miR-516-3p) to ER(+)/LNN breast cancer aggressiveness (n = 147) and one miRNA (miR-210) to metastatic capability in ER(-)/LNN breast cancer (n = 114) and in the clinically important triple-negative subgroup (n = 69) (all P < 0.05). Bioinformatic analysis coupled miR-210 to hypoxia/VEGF signaling, miR-7 and miR-516-3p to cell cycle progression and chromosomal instability, and miR-128a to cytokine signaling. In conclusion, our work connects four miRNAs to breast cancer progression and to several distinct biological processes involved therein.

SUBMITTER: Foekens JA

PROVIDER: S-EPMC2529088 | biostudies-other | 2008 Sep

REPOSITORIES: biostudies-other

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Four miRNAs associated with aggressiveness of lymph node-negative, estrogen receptor-positive human breast cancer.

Foekens John A JA Sieuwerts Anieta M AM Smid Marcel M Look Maxime P MP de Weerd Vanja V Boersma Antonius W M AW Klijn Jan G M JG Wiemer Erik A C EA Martens John W M JW

Proceedings of the National Academy of Sciences of the United States of America 20080828 35

In this study, we quantified 249 mature micro-RNA (miRNA) transcripts in estrogen receptor-positive (ER(+)) primary breast tumors of patients with lymph node-negative (LNN) disease to identify miRNAs associated with metastatic capability. In addition, the prognostic value of the candidate miRNAs was determined in ER(-)/LNN breast cancer. Unsupervised analysis in a prescreening set of 38 patients identified three subgroups predominantly driven by three miRNA signatures: an ER-driven luminal B-ass ...[more]

PMID: 18755890

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Project description:IntroductionAlthough lymph node negative (LN-) breast cancer patients have a good 10-years survival (?85%), most of them still receive adjuvant therapy, while only some benefit from this. More accurate prognostication of LN- breast cancer patient may reduce over- and under-treatment. Until now proliferation is the strongest prognostic factor for LN- breast cancer patients. The small molecule microRNA (miRNA) has opened a new window for prognostic markers, therapeutic targets and/or therapeutic components. Previously it has been shown that miR-18a/b, miR-25, miR-29c and miR-106b correlate to high proliferation.MethodsThe current study validates nine miRNAs (miR-18a/b miR-25, miR-29c, miR-106b, miR375, miR-424, miR-505 and let-7b) significantly correlated with established prognostic breast cancer biomarkers. Total RNA was isolated from 204 formaldehyde-fixed paraffin embedded (FFPE) LN- breast cancers and analyzed with quantitative real-time Polymerase Chain Reaction (qPCR). Independent T-test was used to detect significant correlation between miRNA expression level and the different clinicopathological features for breast cancer.ResultsStrong and significant associations were observed for high expression of miR-18a/b, miR-106b, miR-25 and miR-505 to high proliferation, oestrogen receptor negativity and cytokeratin 5/6 positivity. High expression of let-7b, miR-29c and miR-375 was detected in more differentiated tumours. Kaplan-Meier survival analysis showed that patients with high miR-106b expression had an 81% survival rate vs. 95% (P?=?0.004) for patients with low expression.ConclusionHigh expression of miR-18a/b are strongly associated with basal-like breast cancer features, while miR-106b can identify a group with higher risk for developing distant metastases in the subgroup of Her2 negatives. Furthermore miR-106b can identify a group of patients with 100% survival within the otherwise considered high risk group of patients with high proliferation. Using miR-106b as a biomarker in conjunction to mitotic activity index could thereby possibly save 18% of the patients with high proliferation from overtreatment.

Project description:In this study, we aimed to evaluate axillary lymph node dissection (ALND) rates and prognosis in neoadjuvant chemotherapy (NCT) compare with neoadjuvant endocrine therapy (NET) in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-), lymph node (LN)-positive, premenopausal breast cancer patients (NCT01622361). The multicenter, phase 3, randomized clinical trial enrolled 187 women from July 5, 2012, to May 30, 2017. The patients were randomly assigned (1:1) to either 24 weeks of NCT including adriamycin plus cyclophosphamide followed by intravenous docetaxel, or NET involving goserelin acetate and daily tamoxifen. ALND was performed based on the surgeon's decision. The primary endpoint was ALND rate and surgical outcome after preoperative treatment. The secondary endpoint was long-term survival. Among the 187 randomized patients, pre- and post- neoadjuvant systemic therapy (NST) assessments were available for 170 patients. After NST, 49.4% of NCT patients and 55.4% of NET patients underwent mastectomy after treatment completion. The rate of ALND was significantly lower in the NCT group than in the NET group (55.2% vs. 69.9%, P=.046). Following surgery, the NET group showed a significantly higher mean number of removed LNs (14.96 vs. 11.74, P=.003) and positive LNs (4.84 vs. 2.92, P=.000) than the NCT group. The axillary pathologic complete response (pCR) rate was significantly higher in the NCT group (13.8% vs. 4.8%, P=.045) than in the NET group. During a median follow-up of 67.3 months, 19 patients in the NCT group and 12 patients in the NET group reported recurrence. The 5-year ARFS (97.5%vs. 100%, P=.077), DFS (77.2% vs. 84.8%, P=.166), and OS (97.5% vs. 94.7%, P=.304) rates did not differ significantly between the groups. In conclusion, although survival did not differ significantly, more NCT patients might able to avoid ALND, with fewer LNs removed with lower LN positivity.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT01622361, identifier NCT01622361.

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Four miRNAs associated with aggressiveness of lymph node-negative, estrogen receptor-positive human breast cancer.

Publications

Four miRNAs associated with aggressiveness of lymph node-negative, estrogen receptor-positive human breast cancer.

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