Abstract
Estrogen receptor-positive breast cancer is subdivided into subtypes LuminalA and LuminalB, based on different expression patterns. MicroRNA-190b has been reported to be up-regulated in estrogen receptor-positive breast cancers. In this study we aimed to investigate the role of CpG promoter methylation in regulating miR-190b expression and its impact on clinical presentation and prognosis. DNA methylation analysis for the promotor of microRNA-190b was performed by pyrosequencing 549 primary breast tumors, of which 62 were carriers of the BRCA2999del5 founder mutation, 71 proximal normal breast samples and 16 breast derived cell lines. MicroRNA-190b expression was analysed in 67 primary breast tumors, 14 paired normal breast samples and 16 breast derived cell lines. Tissue microarrays (TMAs) were available for ER (n = 436), PR (n = 436), HER-2 (N = 258) and Ki67 (n = 248). MiR-190b had reduced promoter methylation in estrogen receptor-positive breast cancers (P = 1.02e–12, Median values: ER+ 24.3, ER– 38.26) and miR-190b’s expression was up-regulated in a correlative manner (P = 1.83e–06, Spearman’s rho –0.62). Through breast cancer specific survival analysis, we demonstrated that LuminalA patients exhibiting miR-190b hypo-methylation had better survival than other patients (P = 0.034, HR = 0.29, 95% CI 0.09-0.91). We, furthermore, demonstrated that miR-190b hypo-methylation occurs less frequently in ER+ tumors from BRCA2999del5 mutation carriers than in non-mutated individuals (P = 0.038, Χ2 = 4.32, n = 335). Our results suggest that upregulation of miR-190b may occur through loss of promoter DNA methylation during the development of estrogen-receptor (ER) positive breast cancers, and that miR-190b hypo-methylation leads to increased breast cancer specific survival within the LuminalA- subtype but not LuminalB.
Highlights
Breast cancer is a complex, heterogeneous disease with at least five subtypes defined on the basis of genome-wide expression patterns [1,2,3]
ER+ breast cancers, which www.oncotarget.com are classified as luminal subtypes LuminalA (LumA) and LuminalB (LumB), are most commonly treated using agents inhibiting the estrogen receptor or hormone levels [8, 9]. These cancers have fairly good prognosis, though a subset of patients respond poorly to treatment. This is relevant for LumB type breast cancers, which are diagnosed in younger patients, have higher tumorproliferation rates and have worse prognosis compared to LumA patients [5, 10, 11]
We show that miR-190b promoter methylation loss in tumors is strongly associated with miR-190b over-expression and that breast cancer specific survival is better in individuals with hypo-methylated breast tumors of subtype LumA
Summary
Breast cancer is a complex, heterogeneous disease with at least five subtypes defined on the basis of genome-wide expression patterns [1,2,3] These subtypes are thought to emerge through distinct tumor evolutionary paths and due to their diverse clinical outcome, patient prognosis is highly dependent on tumor subtype [4]. ER+ breast cancers, which www.oncotarget.com are classified as luminal subtypes LuminalA (LumA) and LuminalB (LumB), are most commonly treated using agents inhibiting the estrogen receptor or hormone levels [8, 9]. These cancers have fairly good prognosis, though a subset of patients respond poorly to treatment. It is necessary to fully study the Luminal subtypes for better understanding of the oncogenic mechanisms driving these cancers and improving patient outcomes
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