Breast cancer is the most frequently diagnosed malignancy and the second leading cause of cancer mortality in females worldwide [48]. Broadly, breast cancer patients can be classified into estrogen receptor positive (ER+)—corresponding to 70% of total cases—or estrogen receptor negative (ER−) [49,50]. Drug treatment against both types of breast cancer differs from each other, since several drugs are antagonists of estrogen receptors and exerting their functions blocking binding between ER and estrogens. This binding leads to disrupting the activation of downstream signaling pathway dependent of RE-estrogens interaction [51]. Currently, administration of three drugs, tamoxifen (TMX), doxorubicin (DOX), and paclitaxel (PTX), are considered as first-line of chemotherapy [52]. The application of any of these drugs separately or in combination with different types of drugs that enhance their cytotoxicity against malignant cells, considerably improves the clinical outcome of breast cancer, even though their continuous use results in acquired resistance of breast cancer cells against drug treatment [53,54,55]. To reverse such resistance and re-sensitize cells to different drugs, it is vitally important to understand the underlying molecular mechanisms that modulate their resistance acquisition. Several studies have pointed out the role of H19 as a powerful oncogenic agent in this process, pinpointing it as a critical modulator of chemoresistance (Figure 1).

Paclitaxel (PTX) is the most commonly used antitumor treatment drug on several types of carcinomas [55]. Mechanistically, PTX action includes several signaling pathways in which PTX modulates cellular processes that results in programmed cell death triggering. PTX is considered as the first-line treatment drug in breast cancer (BC), especially in triple negative breast cancer (TNBC) [56], since this subtype of carcinoma is not sensitive to estrogen receptor positive breast cancer cell. Unfortunately, the resistance of BC to PTX treatment is a great obstacle in clinical applications and one of the major causes of death associated with treatment failure. In breast cancer, PTX (Figure 1A) induces cellular apoptosis by interacting with β-tubulin and altering microtubules stability. PTX-resistance is acquired by mutations in α or β-tubulin, enhancing p53 and AKT activation signaling pathways or by dysregulation of apoptotic proteins [57,58]. Functional assays in both ER(+)-MCF-7 and ER(-)-Triple negative breast cancer (TNBC) carcinomas have shown that acquisition of resistance to PTX requires the upregulation of H19 (Figure 1B), which in turn blocks activation of several apoptotic pathways. Curiously, in ERα + breast cancer, H19 modulates resistance of PTX at both transcriptional and post-transcriptional levels. Si et al. (2016) [59] demonstrated that upregulation of H19 in MCF-7 cell line inhibited transcription of BCL-2 interacting killer protein (BIK)—a proapoptotic BH3-only member of the BCL-2 family which is prognostic for relapse and decreased overall survival of breast cancer [60]—by recruiting EZH2 subunit to the promoter of this gene, modulating H3 methylation at lysine 27. As result of BIK promoter methylation, PTX-resistance MCF-7 cells display increased proliferation rate and decreased cellular apoptosis [59]. Furthermore, H19 blocks miR-340-3p function—a known tumor suppressor miRNA involved in repression of EMT—acting as competitive sponge and avoiding degradation of tyrosine 3-monooxygenase/tryptophan 5-monoixygenase activation protein (YWHAZ), which in turn enhances activation of Wnt/β-catenin signaling pathway. As results of increased activity of YWHAZ-Wnt/β-catenin axis, PTX-resistance cells exhibit increased metastasis, invasion, and EMT. Additionally, the phenotype associated with H19 upregulation is recapitulated in both xenograft models and biopsies from patients with PTX resistance [61]. Unlike ER(+), increased H19 levels in TNBC promote activation of AKT by phosphorylation. As a consequence of enhancing AKT activity, BAX and cleaved caspase 3 are repressed, and cellular apoptosis is inhibited. Furthermore, downregulation of H19 in TNBC is translated into lower tumor growth rate in vivo and reduced cell proliferation accompanied by higher rates of apoptosis [62].

Doxorubicin (DOX) is a member of the anthracycline family and currently is one of the main treatments of choice for the treatment of both ER+ and ER- breast cancer [54]. DOX negatively affects the survival of malignant cells through different mechanisms of action (Figure 1A): (1) DOX is capable of mediating intercalation into DNA and disruption of topoisomesare-II function, avoiding DNA repair, and increasing cellular apoptosis; (2) DOX promotes generation of free radicals and their damage to cellular membranes, proteins, and DNA; (3) DOX deregulates several pivotal pathways involved in tumorogenesis such as PI3K/mTOR/AKT or ERK signaling [63]. Several studies have pointed out H19 as a major mediator of DOX chemoresistance (Figure 1C) by modulating MDR1/MDR4 and PARP1 expression [64,65]. Increased expression of H19 is required for the acquisition of DOX-resistance in several breast cancer cell lines. Curiously, downregulation of H19 reduces cell viability, lowers colony forming, and increases apoptosis under DOX treatment. Mechanistically, H19 promotes expression of Cullin 4A (CUL4A), a ubiquitin ligase component [66], which in turn enhances expression of ABCB1/4 genes that encoded MDR1/4 proteins, two members of the ATP-binding cassette family highly upregulated in several carcinomas, including breast cancer [67,68]. Both proteins exert pivotal functions in oncogenesis acting as inductors of multidrug resistance [69]. However, the molecular mechanisms dependent on MRD1/MDR4 are still unclear and require additional and intensive investigations. Wang et al. (2020) [65] showed that H19-induced DOX-chemoresistance is mediated by repression of PARP1. In MCF-7, high levels of H19 were correlated with downregulated PARP1 expression. Even though PARP1 is upregulated in several types of carcinomas and PARP1 inhibitors have been described as pivotal drugs against tumorigenesis, PARP1 has been shown to increase the antitumor activity of other drugs such as temozolomide and topotecan in preclinical studies, including models of pediatric cancers [70,71,72]. Curiously, it is capable of being packaged into exosomes from resistance cells and this diffusion towards sensitive cells leads to the acquisition of resistance against DOX treatment [73].

Tamoxifen (TMX), an anti-estrogen (Figure 1A), competitively inhibits estrogen binding to the ER and blocks the ER-mediated stimulation signal [53]. Five years of tamoxifen adjuvant therapy has been shown to safely reduce 15-year risk of breast cancer recurrence and death; however, a substantial group of patients was shown to eventually develop resistance (de novo or acquired) to tamoxifen. Although many molecular mechanisms of tamoxifen resistance have been described, including mutations in the ESR1 gene and the activation of alternative growth pathways, such as ERBB2/HER2, EGFR, IGF1R, and cyclin D1/CDK4/6 pathways, it remains necessary to gain an improved understanding of the potential mechanisms of tamoxifen resistance [74,75,76,77]. Several studies have pointed out the importance of upregulation of H19 in TMX resistance acquisition. Increased level of H19 in TMX-resistance cells (Figure 1D) is translated into enhanced autophagy activity and higher metabolism ratio by upregulation of Beclin1 (BECN1) and downregulation of N-acetyltransferase-1 (NAT1) transcription, respectively [78,79]. H19 downregulates the methylation state of Beclin1 promoter by binding and inhibiting S-adenosyl homocysteine hydrolase (SAHH). As consequence, DNMT3B function is reduced, resulting in lower ratio of methylation of Beclin1 promoter and thus higher Beclin1 expression [78]. Additionally, H19 modulate methylation of NAT1 promoter reducing transcription of it. NAT1 exert a pivotal role in metabolism of carcinogens and it is negatively correlated with a poor prognosis and aggressiveness of ER(+) breast cancer [79].