**2.2 HER2(+) breast cancer**

Human Epidermal Growth Factor Receptor 2 (Her2) protein is a transmembrane receptor tyrosine kinase, which is a member of the EGFR family and plays an important role in mitogen signaling. Amplification of this receptor plays an important role in BC. Overexpression of the Her2 protein results from the Erb-B2 Receptor Tyrosine Kinase 2 (*ERBB2*) gene amplification of all BC tumors (known as HER2-positive BC) [52]. *Her2* overexpression is caused by overactivation of the downstream phosphatidylinositol 3-kinase/ protein kinase B (PI3K/Akt), *Phospholipase* C, gamma 1 *(PLC-γ),* and mitogen-activated protein kinase (*Mapk)* pathways, leading to increased tumor cell growth, survival, motility, and invasion [53]. *HER2* amplification and/or overexpression causes its conversion from a protoncogene to an oncogene. This has important effects on the metastasis of BC. Clinical studies show that amplification of *HER2* has a significantly worse prognosis in BC patients compared to patients with unamplified *HER2* [54]. In addition to the presence of HER2 in the membrane, it is also found in the nucleus at a lower rate than in the membrane. Despite low HER2 in the nucleus, it is thought to have important roles in the nucleus and chromatin [55]. HER2 is transported to the nucleus by endocytosis via importin β1 and the nuclear pore protein (NUP358) [56]. When HER2 enters the nucleus, it joins forces with PR and Activator protein 1 (AP-1) to activate the transcription factor Signal transducer and activator of transcription 3 (STAT3) in a complex [57, 58]. HER2 interacts with RNA pol I and actin, which enhanced growth by increasing the transcription of the rRNA gene [59]. In another study, it was reported that HER2 binds to the Cyclooxygenase (COX) promoter, which is associated with several malignant tumors found in SK-BR-3 (Skbr3) and BT-474 BC cell lines [60]. In a sizable cohort of BC patients, Dillon et al. [61] showed a correlation between *COX-2* expression and *HER2,* and *HER2* predicted poor disease-free survival in patients receiving endocrine therapy.

Tumor cells may become more vulnerable to further genetic harm and develop extensive instability in the tumor genome as a result of early genetic alterations that de-regulate tumor suppressors and oncogenes. Another research reported that comparative genomic hybridization to measure global copy number alterations discovered that HER2-amplified tumors had considerably greater levels of aberrations than HER2-negative tumors, indicating that these cancers were genetically more progressed [62]. The positive correlation between chromosomal changes at chromosomes 11q13.1, 16q22-q24, and 18q21 and HER2 amplification suggests that genes in these regions may be involved in the pathogenesis of HER2+ tumors in addition to the high levels of overall genomic instability associated with *HER2* amplification [63].

Depending on the metastatic stage, cancer cells may employ one or several metabolic pathways [64]. In addition, depending on where they metastasis, cancer cells may adopt a particular metabolic pattern [65]. Cytoplasmic and mitochondrial nuclear crosstalk can regulate the metabolism of BC. Metabolites in the cytoplasm and mitochondria dictate gene transcription and DNA methylation. Numerous transcription factors shuttle between the nucleus and mitochondria to ensure that genes that regulate metabolism are transcribed [66]. *HER2*-mediated signals regulate lactate dehydrogenase-A levels, 6-Phosphofructo-2-kinase levels, and lactate accumulation in tumors because they promote glucose utilization [66–69]. It has been reported that *HER2* can be replaced by the heat shock protein associated with mitochondria (mtHSP70), both in patient samples and in many cell lines. *HER2* in mitochondria has a negative regulatory effect by indirectly promoting glycolysis of oxygen consumption [70]. In another study, higher levels of glycine, succinate, creatinine, and glutamine were observed in *HER2+* tumors compared to *HER2*- tumors, while a decrease in alanine levels was reported [71]. *HER2* promotes the RAS*-*ERK*-*RSK pathways, ensuring cell survival. HER2+ inhibitors of HER2 in the mammary gland cause a decrease in the activity of these pathways. This, in turn, inhibits the survival of the cell. Another way is the AKT*-*mTOR pathway. This pathway causes cell proliferation. The HER2 inhibitor causes a decrease in the activity of this pathway. The rapamycin and rapalogs inhibit the activity of mTOR, such as in HER2+ BC, and prevent the phosphorylation of S6K, the process inhibits cell proliferation and reduces aerobic glycolysis as the result of the downregulation of glycolytic enzymes. In addition, the glucose analog 2-deoxy-D-glucose (2-DG) inhibits mTOR signaling by activating PI3K signaling, suppressing aerobic glycolysis, and phosphorylating AMPK on T172 [72].

*HER2* expression in epithelial-like BC cells is significantly higher than in mesenchymal-like BC cells. This is because of the open/active chromatin of the *ERBB2* gene in epithelial-like cells, as well as the closed/inactive chromatin of the *ERBB2* gene in mesenchymal-like BC cells. The chromatin-based epigenetic silencing of the *ERBB2* gene in the EMT of HER2+ BC cells causes inhibition of *HER2* expression, which in turn leads to the emergence of resistance to anti-*HER2* monoclonal antibodies such as trastuzumab [73]. In this study, the H3K9ac and H3K27me3 epigenetic profiles and microanalysis of genes enriched with the promoter h3k9ac chip revealed epi-promoter regions of genes modified by mark at HER2+ and TNBC tumors. The H3K9ac modification has been reported to induce downregulation of most of the related genes in *HER2*-amplified tumors [74]. Descriptive investigations of the HER2/neu epigenetics in BC support the repression of *Her2/neu* by increased H3K9me2. Lim et al. demonstrated that the histone demethylase Kdm1, which removes the methyl groups from dimethylated H3K9, directly targets *Her2/neu*. In this instance, siRNA mediates *Kdm1* knockdown and reduces *Kdm1* accumulation on the *Her2/neu* promoter, which increases H3K9 methylation, decreases *Her2/neu* expression, and inhibits the proliferation of the treated BC cell lines [75]. In another study, it was determined that LAQ824 treatment caused the activation of Her2/neu transcriptional repressor, and acetylation of HSP90, on the other hand, it caused phosphorylated mitogen-activated protein kinase levels and hyperacetylation of HSP 90 with a labile chaperone complex. LAQ824 indirectly marked the Her2/neu protein for proteasomal degradation [45]. For several primary cancers, endocrine organs are metastatic targets. Primary tumors can spread directly or metastasize through the lymphatic and arterial routes. Melanomas, breast, and lung carcinomas are the primary tumors that metastasize to the adrenals most frequently. These tumors can cause adrenal insufficiency, especially

*Molecular Mechanisms of Breast Cancer Metastasis DOI: http://dx.doi.org/10.5772/intechopen.108424*

when both adrenals are affected. The most typical primary malignancies that metastasize to the pituitary are breast and lung tumors, which cause pituitary dysfunction in around 30% of cases [76].

Further, cyclin-dependent kinase pathways of PI3K/AKT may lead to endocrine resistance in treatments. Estrogen activity at the molecular level can induce activation of the PI3K/AKT and MAPK pathways at the cell surface and decrease ER and PgR expression [77]. Upregulation of the PI3K/AKT/mTOR pathway contributes to anti-estrogen resistance by promoting survival, tumor cell growth, motility, and metabolism. In this case, the ER promotes transcriptional activity [78]. The intrinsic properties of tumor cells, both soluble factors and ECM proteins from the microenvironment influence the response to Her2-targeted lapatinib or neratinib (TKI). In a study of growing cells on microenvironment microarrays (MEMA), both soluble and ECM factors from various microenvironments were reported to reduce responses to Her2-targeted TKIs. In addition, resistance-conferring factors differed between luminal-like (L-*Her2+*) and basal-like (*Her2E*) *Her2+* subtypes as defined (Cancer Genome Atlas Network, 2012). Microenvironment-mediated resistance was reversed when pertuzumab-treated L-*Her2+* cells co-treated with crizotinib in *HER2E* cells. Hepatocyte growth factor and neuregulin1–1 conferred resistance in *HER2E cells*, but not vice versa, in L-*Her2*+ subtype cells. These varied responses to microenvironmental variables are the result of basic variations in the design and wiring of the signaling networks between the two subtypes. In *L-HER2+* cells and *HER2E* cells, co-treatment with crizotinib and pertuzumab successfully restored the microenvironmentmediated resistance. The findings in this study were consistent with studies that showed that *HER2E* and *L-HER2*+ represent different diseases. The results suggest that *Her2+* subtype-specific approaches to block resistive microenvironmental signals may enhance clinical management of *Her2+* BC with *Her2-*targeted TKIs lapatinib and neratinib [79].
