Dormancy in Breast Cancer, the Role of Autophagy, lncRNAs, miRNAs and Exosomes

Abstract

Breast cancer (BC) is the most frequently diagnosed cancer in women for which numerous diagnostic and therapeutic options have been developed. Namely, the targeted treatment of BC, for the most part, relies on the expression of growth factors and hormone receptors by these cancer cells. Despite this, close to 30% of BC patients may experience relapse due to the presence of minimal residual disease (MRD) consisting of surviving disseminated tumour cells (DTCs) from the primary tumour which can colonise a secondary site. This can lead to either detectable metastasis or DTCs entering a dormant state for a prolonged period where they are undetectable. In the latter, cells can re-emerge from their dormant state due to intrinsic and microenvironmental cues leading to relapse and metastatic outgrowth. Pre- and clinical studies propose that targeting dormant DTCs may inhibit metastasis, but the choice between keeping them dormant or forcing their “awakening” is still controversial. This review will focus on cancer cells’ microenvironmental cues and metabolic and molecular properties, which lead to dormancy, relapse, and metastatic latency in BC. Furthermore, we will focus on the role of autophagy, long non-coding RNAs (lncRNAs), miRNAs, and exosomes in influencing the induction of dormancy and awakening of dormant BC cells. In addition, we have analysed BC treatment from a viewpoint of autophagy, lncRNAs, miRNAs, and exosomes. We propose the targeted modulation of these processes and molecules as modern aspects of precision medicine for BC treatment, improving both novel and traditional BC treatment options. Understanding these pathways and processes may ultimately improve BC patient prognosis, patient survival, and treatment response.

Metastasis in Neuroblastoma and Its Link to Autophagy

“…This study aimed to link compounds and molecular players evidenced in the literature that orchestrate or affect autophagy in various steps of metastasis in NB, as shown in Figure 1 . The concepts presented in this figure can be categorised into four steps in cancers, including NB [ 21 , 23 , 25 , 26 , 49 ]: (1) in the pre-metastasis step, autophagy has a dual effect on promoting or suppressing this process by increasing resistance to drug therapy, including TRAIL or limiting pro-metastasis inflammatory responses, respectively; (2) during the intravasation step, autophagy can promote metastasis by inducing anoikis resistance; (3) during the extravasation step, autophagy can promote dormancy, resistance to drug therapy including TRAIL and survival of tumour cells; and (4) while in the distant metastasis site, autophagy can limit the dimension of the micrometastasis or instead promote metastatic outbreak and expansion [ 21 , 23 , 25 , 26 , 49 ]. Henceforth, the metastasis steps linked to the compounds and molecular players introduced in this review will be further analysed from the viewpoint of their specific cellular role.…”

Dormancy, stemness, and therapy resistance: interconnected players in cancer evolution

“…Exosomes are intraluminal vesicles with an average diameter of 100 nm that contain intracellular components including proteins, microRNAs (miRNAs), and messenger RNAs. Exosomes play a critical role in cancer cell communication and unsurprisingly are emerging as important mediators of chemoresistance, EMT, and dormancy [106,120,121]. The effects of miRNAs shuttled within exosomes have been studied particularly in breast cancer, where miR-23b and miR-222/223 have been shown to induce a dormant phenotype in tumor cells [122,123].…”

“…AMP-activated protein kinase; IGF, insulin-like growth factor; VEGF, vascular endothelial growth factor; IL, interleukin; KDM, lysine-specific demethylase; TET2, ten-eleven translocation 2; lncRNA, long noncoding RNA; miRNAs, EMT-associated factors: vimentin, SNAI1/2, N-cadherin, TWIST, TG2, ZFP281, ZEB1 Colorectal cancer, ovarian cancer, lung cancer, breast cancer[12,41,45,58,62,89,90] Autophagy associated factors: mTOR, beclin1 and VPS34, LKB1-AMPK, IGF2, VEGF, IL8, and IGF1Colorectal cancer, breast cancer, lung cancer, ovarian cancer, osteosarcoma[24,50,74,76,[91][92][93] DNA methylation, DNA oxidation, histone modifications Head and neck squamous cell carcinoma, prostate cancer, breast cancer, glioblastoma[39,40,64,82,94,95] Other epigenetic factors: KDM1B, 2, 3, 5, 6, 7; TET2 Glioblastoma, colorectal cancer, melanoma, lung cancer, breast cancer[15,[96][97][98][99][100][101][102][103][104] lncRNAs and miRNAsBreast cancer[105][106][107] …”

Extracellular Vesicles in Breast Cancer: From Biology and Function to Clinical Diagnosis and Therapeutic Management

“…Evidence has accumulated over recent years that the PVN in BC orchestrates CTC dormancy, principally responsible for cell survival and growth arrest [ 339 ]. CTCs may receive intrinsic factors (microenvironmental factors and signaling molecules) relevant to dormancy [ 340 ]. In bone marrow representing a niche for BC cell homing, SEVs from surrounding MSCs contain specific miRNAs that drive metastatic BC cells to dormancy.…”