**2.3 TNBC (HER-, ER-, PR-)**

TNBC forms 10–15% of all BCs [80]. The cells from this subtype test as negative for the receptors of estrogen and progesterone hormones and also for HER2 protein [80]. When compared to other types that are hormone receptor-positive and HER2+, TNBC is generally more aggressive while being difficult to treat with its insufficient treatment options since hormonal therapy medicines or medicines that target HER2 protein is not available for this situation [81]. TNBC also shows to have a worse prognosis due to the development of metastasis in secondary organs like the brain, lungs, and bone [82]. The complexity in the metastatic process when combined with the lack of targeted therapy makes this disease a harder one to cure. Besides these problems, it is also found to be more likely to reoccur. But its symptoms, staging, diagnosis, and survival are similar to other invasive ductal carcinomas [83].

The basal-like subtype of BC is characterized by high proliferation, high histological grade, and poor prognosis. And this subtype can be triple negative although not all of the basal-like cancers resemble the forms that express ER and HER2 [82]. By gene expression profiling, TNBC is also identified with seven subtypes: two basal-like (BL1 and BL2), a mesenchymal (M), a mesenchymal-stem cell-like, an immunomodulatory, a luminal androgen receptor/luminal-like, and an unclassified type. And each subtype shows unique ontologies and different responses to standard-of-care chemotherapy [84]. Besides the differences, TNBC is generally found to be responding less to conventional chemotherapy while the patients carry a bigger risk of recurrence and relapse [85].

Non-coding RNAs (ncRNAs) may have a role in the progression of BC cases and the metastasis process. And in the process of forming miRNAs, Heterogeneous nuclear ribonucleoproteins A2/B1 (*HNRNPA2B1*) interacting with a component of the DROSHA complex is known to stimulate the processing of pri-miRNA to premiRNAs [86]. Also, *HNRNPA2B1* transcript and protein expression were found to be high in BC cells and tumors when compared to nontransformed cell lines and normal breast tissue. With the TNBC subtype, it is shown that MDA-MB-231 TNBC cells with *HNRNPA2B1* knockout have reduced tumor growth but were stimulated in metastasis when injected into mice. So, the role is not clear with *HNRNPA2B1* but it is essential to research deeply to understand its role in BC metastasis. Also, using the sublines of MDA-MB-468 TNBC cells, drivers of metastasis are identified as IL11 and VEGF-D in *in vivo*. They activate the effector neutrophils and promote metastatic niche [87]. In this case, chemotherapy may have a negative effect by increasing the metastatic potential if the cells with innate resistance are selected.

MetastamiRs are the miRNAs have a pro- or anti-metastatic effect [88]. Prometastatic miRNAs are expressed higher in breast tumors showing a link to reduced disease-free survival (DFS) and survival by miR-9-5p is one of them as a pro-metastatic oncomiR and found to be at a higher level in TNBC than other subtypes. miR-373, miR-29a/b/c, and miR-19a are all found to be pro-metastatic and with a high level in TNBC subtypes. miR-206, and miR-31-5p are listed as anti-metastatic with a lower expression in TNBC subtypes. But miR-20a-5p which also is listed as antimetastatic has a higher expression in TNBC compared to other types [87]. All of the miRNAs affect the regulation of the metastasis process. The increased expression of miR-520c-3p is observed in MDA-MB-231 TNBC cells. And it is found to be inhibiting TGF-β signaling which can be related to inhibiting phosphorylation of suppressors against decapentaplegic 2 (SMAD2) and decapentaplegic 3 (SMAD3) and decreases target genes *ANGPTL3*, *PTHLH*, and *SERPINE1* (*PAI-1*) [89]. miR-373 is another miRNA that is pro-metastatic and with its increased expression, MDA-MB-435 cell migration and invasion are induced in *in vitro*. It has also been found to be promoting tumor metastasis observed via tail vein injection mouse model [87]. Some genes are found to be linked with TNBC metastasis. In a study, 26 hub genes were identified as metastasis-associated candidate genes [90]. In-depth studies with four of them, Immunoglobulin Superfamily Member 10 (*IGSF10*), Runt-related transcription factor 1 translocation partner 1 (*RUNX1T1*), X-inactive specific transcript (*XIST*), and transcription factor teeshirt zinc finger homeobox 2 (*TSHZ2*) indicated that they were downregulated in TNBC tissues and these genes have prognostic and diagnosis values in TNBC [90]. *IGSF10* is an immunoglobulin superfamily member 10 normally associated with developmental processes and differentiation [91]. By whole-exome sequencing it was found to be a potential cancer-related gene *RUNX1T1* is a member of the mind the gap (*MTG*) family. It was already known to be reported in many cancer types as a novel biomarker or as being vital for tumorigenesis. *XIST* plays a role in the inactivation of the X chromosome. It was also known to have a relationship with cancer cases since its expression was observed to be dysregulated in some cases. *TSHZ2* is a member of the TSHZ family and like the others, its expression was observed in other cancer types and was found to have a downregulation in some cancers [90].

With the studies done in TNBC, it is found that this subtype is possess more therapy-resistant Cancer Stem Cells (CSC) when compared to other subtypes. The difference in mortality and recurrence rates with the therapy failures may be the result of this difference in CSC enrichment in TNBC. So, studying cellular signaling
