MicroRNAs in breast cancer initiation and progression

Abstract

The emerging role of microRNAs (miRNAs) in the epigenetic regulation of many cellular processes has become recognized in both basic research and translational medicine as an important way that gene expression can be fine-tuned. Breast cancer is the most frequent cancer in women, with about one million new cases diagnosed each year worldwide. Starting with the early work of miRNA profiling, more effort has now been put on functions of miRNAs in normal mammary stem cells, breast cancer initiating cells and metastatic cells, and therapy-resistant cancer cells. Future translational studies may focus on identifying miRNA signatures as cancer biomarkers and developing miRNA-based targeted therapeutics.

Fig. 1

A summary of miRNA regulators and biomarkers in the development of the normal mammary gland, breast cancer initiation, metastasis, and therapy resistance. In these four processes, mammary stem cells (MaSC), breast cancer stem cells (BCSCs), metastatic CSCs (MCSCs), and therapy-resistant CSCs (TRCSCs) are pivotal originators and/or critical cell players. The top panels list miRNA regulators, including suppressor-miRs in green and oncomiRs in red, in normal mammary gland development (MaSCs-originated), breast cancer initiation (BCSCs-mediated), breast cancer metastasis, and therapy resistance, respectively. These tumor-inhibiting suppressor-miRs and tumor-promoting oncomiRs are promising candidates for therapeutic intervention as miR replacement therapy or antagomirs. The bottom panels list miRNA biomarkers, coded as up-regulated miRs in red and down-regulated miRs in green, which showed differential expression in normal MaSCs/mammary glands and primary breast tumors compared to distinct counterparts: (1) In MaSC panel, let-7b/c, miR-205, -22, -93, and -200 are differentially expressed in MaSCs and/or mammary progenitors compared to differentiated epithelial cells; miR-138, -431, and -133a/b are related to mammary glands during pregnancy and lactation, compared to virgin and involuting glands. (2) Br Ca (breast cancer) panel presents differentially expressed miRs in breast cancer versus normal breast tissue. (3) ER/PR panel displays miRs related to ER or PR status (ER⁺ or PR⁺ tumors vs. ER⁻ or PR⁻ tumors respectively). (4) Invasion panel shows down-regulated miRs in tumors with lymph node metastasis (let-7 and miR-9-3) or vascular invasion (miR-10b, miR-123, miR-29a, miR-205, etc.). (5) DRFS panel includes up- and down-regulated miRs related to high risk or poor prognosis of ER⁺ and ER⁻ breast tumor patients. (6) Drug resistance panel lists miRs (a few with direct target genes) related to drug resistance of breast cancer cells or primary tumors, such as tamoxifen resistance of MCF-7 cells and HER2⁺/ER⁻ tumors (miR-221/222), paclitaxel resistance of MDA-MB-435 cells 468 cells (miR-221/222, -125b), doxorubicin resistance of MCF-7 cells (miR-127, -34a, -27b, -206, -106a, -21, -214, and let-7), and cisplatin resistance of MCF-7 cells (miR-146, -10a/b, -221/222, -29a/b, -206, -200b/c, -345, -126, -205, and -342)