From Micro to Long: Non-Coding RNAs in Tamoxifen Resistance of Breast Cancer Cells

Abstract

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality among women. Two thirds of patients are classified as hormone receptor positive, based on expression of estrogen receptor alpha (ERα), the main driver of breast cancer cell proliferation, and/or progesterone receptor, which is regulated by ERα. Despite presenting the best prognosis, these tumors can recur when patients acquire resistance to treatment by aromatase inhibitors or antiestrogen such as tamoxifen (Tam). The mechanisms that are involved in Tam resistance are complex and involve multiple signaling pathways. Recently, roles for microRNAs and lncRNAs in controlling ER expression and/or tamoxifen action have been described, but the underlying mechanisms are still little explored. In this review, we will discuss the current state of knowledge on the roles of microRNAs and lncRNAs in the main mechanisms of tamoxifen resistance in hormone receptor positive breast cancer. In the future, this knowledge can be used to identify patients at a greater risk of relapse due to the expression patterns of ncRNAs that impact response to Tam, in order to guide their treatment more efficiently and possibly to design therapeutic strategies to bypass mechanisms of resistance.

Keywords: breast cancer; endocrine resistance; estrogen receptor; lncRNA; microRNA; ncRNA; tamoxifen.

Figure 1

Estrogen signaling and pathways that interfere in tamoxifen resistance.

Figure 2

Percentage of articles found in one or more literature sources. A literature search was performed on PubMed (PM), Science Direct (SC), Medline (MD), and Web of Science (WS) databases using the following keywords: “long non-coding RNA/lncRNA” OR “microRNA/miRNA/miR” AND “tamoxifen resistance/tam-resistance/endocrine resistance”. We represented the final numbers of publications selected in this review. The Medline source had no studies after applying the exclusion criteria.

Figure 3

Schematic representation of study selection divided by microRNAs and long non-coding RNAs in four databases (PubMed, ScienceDirect, Medline, and Web of Science). Keyword variants were used to perform the search (long non-coding RNA; lncRNA; microRNA; miRNA; miR) AND (tamoxifen resistance; tam-resistance; endocrine resistance). Selection was performed based on inclusion criteria: original research papers with miRNA or lncRNA related to tamoxifen resistance, and exclusion criteria: (1): repeated articles between databases that were counted more than once; (2): articles not classified as original research papers, such as: case reports, reviews, book chapters, and meta-analyses; (3): papers wherein miRNAs/lncRNAs were not the focus and these molecules were not properly evaluated. The values inside the central dotted rectangles are the numbers of articles excluded in each selection step, and the external rectangles comprise the final numbers after each selection step. In the end, we obtained two lists of articles for miRNAs and lncRNAs that were analyzed individually (4).

Figure 4

miRNAs, lncRNAs, and target mRNA differentially expressed in resistant breast cancer cells lines. Upregulated miRNAs and lncRNAs are in black, while those downregulated are in orange. Structures of lncRNAs were predicted using the RNAfold tool in the ViennaRNA Package 2.0 and drawn using MFE plain structure drawing. The figure does not contain all regulatory molecules found in this study. The molecules are not to scale.