It is established that the interaction between microenvironment and cancer cells has a critical role in tumor development, given the dependence of neoplastic cells on stromal support. However, how this communication promotes the activation of normal (NFs) into cancer-associated fibroblasts (CAFs) is still not well understood. Most microRNA (miRNA) studies focused on tumor cell, but there is increasing evidence of their involvement in reprogramming NFs into CAFs. Here we show that miR-9, upregulated in various breast cancer cell lines and identified as pro-metastatic miRNA, affects the properties of human breast fibroblasts, enhancing the switch to CAF phenotype, thus contributing to tumor growth. Expressed at higher levels in primary triple-negative breast CAFs versus NFs isolated from patients, miR-9 improves indeed migration and invasion capabilities when transfected in immortalized NFs; viceversa, these properties are strongly impaired in CAFs upon miR-9 inhibition. We also demonstrate that tumor-secreted miR-9 can be transferred via exosomes to recipient NFs and this uptake results in enhanced cell motility. Moreover, we observed that this miRNA is also secreted by fibroblasts and in turn able to alter tumor cell behavior, by modulating its direct target E-cadherin, and NFs themselves. Consistently with the biological effects observed, gene expression profiles of NFs upon transient transfection with miR-9 show the modulation of genes mainly involved in cell motility and extracellular matrix remodeling pathways. Finally, we were able to confirm the capability of NFs transiently transfected with miR-9 to promote in vivo tumor growth. Taken together, these data provide new insights into the role of miR-9 as an important player in the cross-talk between cancer cells and stroma.

Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive neoplasia lacking the expression of hormonal receptors and human epidermal growth factor receptor-2. Accumulating evidence has highlighted the importance of miRNAs dysregulation in the establishment of cancer programs, but the functional role of many miRNAs remains unclear. The description of miRNAs roles might provide novel strategies for treatment. In the present work, an integrated analysis of miRNA transcriptional landscape was performed (N = 132), identifying the significant down-modulation of miR-342-3p in TNBC, probably because of the aberrant activity of estrogen receptor, which serves as a transcription factor of the miRNA, as demonstrated by a siRNA-knockdown approach. The enhanced expression of miR-342-3p significantly decreased cell proliferation, viability and migration rates of diverse TN cells in vitro. Bioinformatic and functional analyses revealed that miR-342-3p directly targets the monocarboxylate transporter 1 (MCT1), which promotes lactate and glucose fluxes alteration, thus disrupting the metabolic homeostasis of tumor cells. Optical metabolic imaging assay defined a higher optical redox ratio in glycolytic cells overexpressing miR-342-3p. Furthermore, we found that hypoxic conditions and glucose starvation attenuate miR-342-3p expression, suggesting a crosstalk program between these metabolic factors. Consistently, miR-342-3p down-modulation is associated with an increased MCT1 expression level and glycolytic score in human triple negative tumors. Overall, we described for the first time the regulatory activity of miR-342-3p on relevant metabolic carcinogenic pathways in TN breast cancers.

Despite its controversial roles in different cancer types, miR-205 has been mainly described as an oncosuppressive microRNA (miRNA), with some contrasting results, in breast cancer. The role of miR-205 in the occurrence or progression of breast cancer has been extensively studied since the first evidence of its aberrant expression in tumor tissues versus normal counterparts. To date, it is known that the expression of miR-205 in the different subtypes of breast cancer is decreasing from the less aggressive subtype, estrogen receptor/progesterone receptor positive breast cancer, to the more aggressive, triple negative breast cancer, influencing metastasis capability, response to therapy and patient survival. In this review, we summarize the most important discoveries that have highlighted the functional role of this miRNA in breast cancer initiation and progression, in stemness maintenance, in the tumor microenvironment, its potential role as a biomarker and its relevance in normal breast physiology—the still open questions. Finally, emerging evidence reveals the role of some lncRNAs in breast cancer progression as sponges of miR-205. Here, we also reviewed the studies in this field.

The clinical management of breast cancer reaches new frontiers every day. However, the number of drug resistant cases is still high, and, currently, this constitutes one of the major challenges that cancer research has to face. For instance, 50% of women affected with HER2 positive breast cancer presents or acquires resistance to trastuzumab. Moreover, for patients affected with triple negative breast cancer, standard chemotherapy is still the fist-line therapy, and often patients become resistant to treatments. Tumor microenvironment plays a crucial role in this context. Indeed, cancer-associated stromal cells deliver oncogenic cues to the tumor and vice versa to escape exogenous insults. It is well known that microRNAs are among the molecules exploited in this aberrant crosstalk. Indeed, microRNAs play a crucial function both in the induction of pro-tumoral traits in stromal cells and in the stroma-mediated fueling of tumor aggressiveness. Here, we summarize the most recent literature regarding the involvement of miRNAs in the crosstalk between tumor and stromal cells and their capability to modulate tumor microenvironment characteristics. All up-to-date findings suggest that microRNAs in the TME could serve both to reverse malignant phenotype of stromal cells, modulating response to therapy, and as predictive/prognostic biomarkers.

Oxidative stress is a pathological condition determined by a disturbance in reactive oxygen species (ROS) homeostasis. Depending on the entity of the perturbation, normal cells can either restore equilibrium or activate pathways of cell death. On the contrary, cancer cells exploit this phenomenon to sustain a proliferative and aggressive phenotype. In fact, ROS overproduction or their reduced disposal influence all hallmarks of cancer, from genome instability to cell metabolism, angiogenesis, invasion and metastasis. A persistent state of oxidative stress can even initiate tumorigenesis. MicroRNAs (miRNAs) are small non coding RNAs with regulatory functions, which expression has been extensively proven to be dysregulated in cancer. Intuitively, miRNA transcription and biogenesis are affected by the oxidative status of the cell and, in some instances, they participate in defining it. Indeed, it is widely reported the role of miRNAs in regulating numerous factors involved in the ROS signaling pathways. Given that miRNA function and modulation relies on cell type or tumor, in order to delineate a clearer and more exhaustive picture, in this review we present a comprehensive overview of the literature concerning how miRNAs and ROS signaling interplay affects breast cancer progression.

Breast cancer that highly expresses human epidermal growth factor receptor 2 (HER2+) represents one of the major breast cancer subtypes, and was associated with a poor prognosis until the introduction of HER2-targeted therapies such as trastuzumab. Unfortunately, up to 30% of patients with HER2+ localized breast cancer continue to relapse, despite treatment. MicroRNAs (miRNAs) are small (approximately 20 nucleotides long) non-coding regulatory oligonucleotides. They function as post-transcriptional regulators of gene expression, binding complementarily to a target mRNA and leading to the arrest of translation or mRNA degradation. In the last two decades, translational research has focused on these small molecules because of their highly differentiated expression patterns in blood and tumor tissue, as well as their potential biological function. In cancer research, they have become pivotal for the thorough understanding of oncogenic biological processes. They might also provide an efficient approach to early monitoring of tumor progression or response to therapy. Indeed, changes in their expression patterns can represent a flag for deeper biological changes. In this review, we sum up the recent literature regarding miRNAs in HER2+ breast cancer, taking into account their potential as powerful prognostic and predictive biomarkers, as well as therapeutic tools.