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Review
. 2015 Oct 14;16(10):24243-75.
doi: 10.3390/ijms161024243.

The Role of MicroRNAs as Predictors of Response to Tamoxifen Treatment in Breast Cancer Patients

Nina G Egeland  1   2 , Siri Lunde  3 , Kristin Jonsdottir  4 , Tone H Lende  5   6 , Deirdre Cronin-Fenton  7 , Bjørnar Gilje  8 , Emiel A M Janssen  9   10 , Håvard Søiland  11   12
Affiliations
Review

The Role of MicroRNAs as Predictors of Response to Tamoxifen Treatment in Breast Cancer Patients

Nina G Egeland et al. Int J Mol Sci. .

Abstract

Endocrine therapy is a key treatment strategy to control or eradicate hormone-responsive breast cancer. However, resistance to endocrine therapy leads to breast cancer relapse. The recent extension of adjuvant tamoxifen treatment up to 10 years actualizes the need for identifying biological markers that may be used to monitor predictors of treatment response. MicroRNAs are promising biomarkers that may fill the gap between preclinical knowledge and clinical observations regarding endocrine resistance. MicroRNAs regulate gene expression by posttranscriptional repression or degradation of mRNA, most often leading to gene silencing. MicroRNAs have been identified directly in the primary tumor, but also in the circulation of breast cancer patients. The few available studies investigating microRNA in patients suggest that seven microRNAs (miR-10a, miR-26, miR-30c, miR-126a, miR-210, miR-342 and miR-519a) play a role in tamoxifen resistance. Ingenuity Pathway Analysis (IPA) reveals that these seven microRNAs interact more readily with estrogen receptor (ER)-independent pathways than ER-related signaling pathways. Some of these pathways are targetable (e.g., PIK3CA), suggesting that microRNAs as biomarkers of endocrine resistance may have clinical value. Validation of the role of these candidate microRNAs in large prospective studies is warranted.

Keywords: biomarker; breast cancer; endocrine resistance; microRNA; tamoxifen.

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Figures

Figure 1
Figure 1
Simplified possible molecular signaling pathways (1 to 6) of estrogen (E) and estrogen receptors (ER). (1) Classical and direct pathway: ligand activation is followed by binding to the estrogen response element (ERE), including coactivators (CoA) and histone acetyl transferases (HATs) before gene regulation is modified; (2) tethered pathway: ligand dependent pathway which includes protein-protein interaction with other transcription factors, e.g., activator protein 1 (Ap1) and specificity protein 1 (Sp1), after ligand activation, thereby regulating genes by indirect DNA binding following serum response element (SRE) activation of transcription; (3) non-genomic ligand dependent reaction: the receptor (e.g., classical ER, ER isoform or other receptors) is activated by a ligand, which may be associated with the membrane. This is then followed by signaling cascades initiated by second messengers (SM), initiating a rapid physiological response, which does not involve gene regulation; (4) ligand-dependent reaction: ER is methylated by ligand induction and ER–phosphoinositide 3-kinase (PI3K)–steroid receptor coactivator (SRC)-focal adhesion kinase (FAK) forms a complex that further activates the serine/threonine–protein kinase Akt, which then activates transcription without ER binding to DNA; (5) ligand independent reaction: ER–SRC–proline-, glutamic acid and leucine-rich protein 1 (PELP1) forms a complex which then activates transcription, also without ER binding to DNA; (6) another ligand independent reaction activates through other signaling pathways, like growth factor signaling by downstream events of receptor tyrosine kinase (RTKs), such as epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2) and the insulin-like growth factor receptor (IGFR) [11,23].
Figure 2
Figure 2
Overview of the adjuvant endocrine treatment guidelines for ER+ breast cancer patients according to the Norwegian Breast Cancer Group (NBCG) 2015 [24], and based on international recommendations (St. Gallen, 2013). There are two options for premenopausal patients (1 and 2 on the left side) and five options for postmenopausal patients (1–5 on the right side) comprising aromatase inhibitor (AI), tamoxifen and ovarian function suppression (OFS) alone or in combination. Total duration of endocrine treatment for a premenopausal patient that becomes postmenopausal after two or five years on tamoxifen (example) is illustrated in brackets. The choice between alternatives 1–5 is made individually based upon tumor biology, side effects and preferences among clinicians and patients. Peri: perimenopausal; TAM: tamoxifen; Yrs: years; Dotted line: years on tamoxifen; Solid line: years on AI.
Figure 3
Figure 3
The tamoxifen pathway and possible mechanisms of endocrine resistance in breast cancer cells. Prior to entering the breast cancer cell, tamoxifen (T) is metabolized in the liver into the two active metabolites, endoxifen and 4-hydroxytamoxifen (4-OHT). When these metabolites enter the cell (blue background) they can bind to estrogen receptors (ERs), thereby blocking the binding of estrogen. ERs bound to tamoxifen then dimerize, enter the nucleus and bind to estrogen response element (ERE). However, the necessary coactivators will not be recruited by the ER–tamoxifen complex. Only corepressors are recruited, therefore gene transcription is not activated. In tamoxifen resistance, this blocking is compromised due to several possible mechanisms: e.g., changes in activity of the metabolizing enzymes of tamoxifen, loss or modification of ER expression, alternative signaling pathways for proliferation and growth, and alterations in the balance of co-regulatory proteins and altered expression of microRNAs [37,39]. Black arrow: normal estrogen pathway. Blue arrow: tamoxifen pathway. Crossed arrow: disrupted pathway.
Figure 4
Figure 4
IPA networks for miR-26a, network 2 (A), miR-519a, network 1 (B) and miR-210, network 1 (C), centered on the estrogen receptor (ESR1). These networks created by IPA comprise networks with ER as a direct (miR-26a) or indirect (miR-519a and miR-210) target. Shaded boxes refer to direct targets whilst clear boxes refer to indirect targets of the specific miRNA.
Figure 4
Figure 4
IPA networks for miR-26a, network 2 (A), miR-519a, network 1 (B) and miR-210, network 1 (C), centered on the estrogen receptor (ESR1). These networks created by IPA comprise networks with ER as a direct (miR-26a) or indirect (miR-519a and miR-210) target. Shaded boxes refer to direct targets whilst clear boxes refer to indirect targets of the specific miRNA.
Figure 5
Figure 5
IPA networks for miR-30c, network (A), miR-126, network 1 (B) and miR-342, network 2 (C), centered on the estrogen receptor (ESR1). These networks created by IPA, comprise networks with ER as an indirect target (miR-126 and miR-342), whereas miR-30c has an ER-complex as an indirect target. Shaded boxes refer to direct targets whilst clear boxes refer to indirect targets of the specific miRNA.
Figure 5
Figure 5
IPA networks for miR-30c, network (A), miR-126, network 1 (B) and miR-342, network 2 (C), centered on the estrogen receptor (ESR1). These networks created by IPA, comprise networks with ER as an indirect target (miR-126 and miR-342), whereas miR-30c has an ER-complex as an indirect target. Shaded boxes refer to direct targets whilst clear boxes refer to indirect targets of the specific miRNA.
Figure 6
Figure 6
Top networks of miR-30c, network 1 (A), miR-10a, network 1 (B), miR-342, network 1 (C) and miR-26a, network 1 (D). Shown here are networks with the highest scores calculated by IPA, showing direct targets of the miRNAs. Shaded boxes refer to direct targets whilst clear boxes refer to indirect targets of the specific miRNA.
Figure 6
Figure 6
Top networks of miR-30c, network 1 (A), miR-10a, network 1 (B), miR-342, network 1 (C) and miR-26a, network 1 (D). Shown here are networks with the highest scores calculated by IPA, showing direct targets of the miRNAs. Shaded boxes refer to direct targets whilst clear boxes refer to indirect targets of the specific miRNA.
Figure 6
Figure 6
Top networks of miR-30c, network 1 (A), miR-10a, network 1 (B), miR-342, network 1 (C) and miR-26a, network 1 (D). Shown here are networks with the highest scores calculated by IPA, showing direct targets of the miRNAs. Shaded boxes refer to direct targets whilst clear boxes refer to indirect targets of the specific miRNA.
Figure 7
Figure 7
Overview of the possible involvement of candidate microRNAs in tamoxifen resistance pathways, based on the present literature search and IPA analysis. MicroRNAs miR-10a, -26a, -30c, -126, -210, -342-5p and -519a and their direct (pink lines) or indirect (dotted lines) targets. BCL2: B-cell CLL/lymphoma 2; CDK6: cyclin-dependent kinase 6; CYP24A1: cytochrome P450, family 24, subfamily A, polypeptide 1; IGF1: insulin-like growth factor 1; FOXA1: forkhead box A1; HOXA1: homeobox A1; HOXB1: homeobox B1; Hsp90: heat-shock protein 90. KDM3A: lysine (K)-specific demethylase 3A. PAG1: phosphoprotein membrane anchor with glycosphingolipid microdomains 1; PI3K: phosphoinositide 3-kinase; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; PIK3CD: phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta; PIK3R2: phosphoinositide-3-kinase, regulatory subunit 2 (beta); RB1: retinoblastoma 1; TIMP3: TIMP metallopeptidase inhibitor 3; ZEB1: zinc finger E-box binding homeobox 1. Black arrow: normal pathway. Blue arrow: tamoxifen pathway. Crossed arrow: disrupted pathway. Pink inhibition arrow: direct inhibition by miRNA. Dotted pink inhibition arrow: indirect inhibition by miRNA.
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References

    1. Haynes B.P., Viale G., Galimberti V., Rotmensz N., Gibelli B., A'Hern R., Smith I.E., Dowsett M. Expression of key estrogen-regulated genes differs substantially across the menstrual cycle in estrogen receptor-positive primary breast cancer. Breast Cancer Res. Treat. 2013;138:157–165. doi: 10.1007/s10549-013-2426-0. - DOI - PubMed
    1. Baak J.P.A., van Diest P.J., Voorhorst F.J., van der Wall E., Beex L.V.A.M., Vermorken J.B., Janssen E.A.M., Gudlaugsson E., other collaborators of the Multicenter Morphometric Mammary Carcinoma Project (MMMCP) The prognostic value of proliferation in lymph-node-negative breast cancer patients is age dependent. Eur. J. Cancer. 2007;43:527–535. - PubMed
    1. Goldhirsch A., Winer E.P., Coates A.S., Gelber R.D., Piccart-Gebhart M., Thurlimann B., Senn H.J. Personalizing the treatment of women with early breast cancer: Highlights of the St gallen international expert consensus on the primary therapy of early breast cancer 2013. Ann. Oncol. 2013;24:2206–2223. doi: 10.1093/annonc/mdt303. - DOI - PMC - PubMed
    1. Cuzick J., Dowsett M., Pineda S., Wale C., Salter J., Quinn E., Zabaglo L., Mallon E., Green A.R., Ellis I.O., et al. Prognostic value of a combined estrogen receptor, progesterone receptor, ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the genomic health recurrence score in early breast cancer. J. Clin. Oncol. 2011;29:4273–4278. doi: 10.1200/JCO.2010.31.2835. - DOI - PubMed
    1. National Comprehensive Cancer Network (NCCN) [(accessed on 4 October 2015)]. Available online: http://www.nccn.org/

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