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

HER2+ BC than in other subtypes. This indicates that HER2+ BC has the greatest glutamine metabolism activity. Importantly, the lowest expression of stromal *GLS1* and *GDH*, tumoral *ASCT2*, and serine hydroxymethyltransferase 1 were found in the luminal A subtype [18].

Amino acid biosynthesis and degradation, *de novo* nucleotide biosynthesis, reductive metabolism, and methylation are all involved in one-carbon metabolism. This metabolism has long been assumed to play a key role in sustaining tumor cells' high proliferation rate [19]. Additionally, folate (vitamin B9), and other B vitamins like B6 and B12, play an important role in one-carbon metabolism. Although the link between folic acid consumption and the risk of BC is still debated, a recent study found that increasing folate intake reduced the risk of ER-, ER-/PR- [20]. Immunity and tolerance are manipulated by tryptophan and arginine, which are frequently unregulated in malignancies. In BC contexts, the activity of arginase, the primary enzyme that catalyzes L-arginine, is increased, creating an adverse environment for T cell adaptability [21].

The development and progression of BC are dependent on lipid and fatty acids (FAs) metabolism [8]. By enhancing lipid and lipoprotein absorption or increasing cholesterol and lipid synthesis, cancer cells maintain a high rate of proliferation, displaying active lipid and cholesterol metabolisms [22]. Furthermore, the synthesis of FAs causes cancer cells to grow and proliferate faster. Fatty acid synthase (FASN) is a critical enzyme for FAs. When it is overexpressed, cancer proliferation occurs and a poor prognosis is observed in BC. That is why enhanced FAs activity is required for BC progression [23]. SREBP-1, a lipogenic transcription factor, can influence FASN expression by interacting with the *FASN* promoter region. *FASN* expression has also been shown to be influenced by the phosphatidylinositol-3-kinase (PI3K)/ AKT/mTOR and mitogen-activated protein kinase (MAPK) pathways [24]. The *FASN* expression is increased in BC cells because AKT and Sterol Regulatory Element-Binding Protein 1 (*SREBP-1*) are activated under hypoxic environments. Finally, inhibiting the MAPK pathway or using the mTOR inhibitor rapamycin can lower the expression of *FASN* in BC cells [25].

The signaling pathway of PI3K/AKT/mTOR is important for the cell cycle and metabolism in cancer development. Signals from growth factors, nutrients, energy signals, and various stress signals under hypoxia or DNA damage that provide growth and division of cells are integrated by the mammalian target of rapamycin complex 1 (mTORC1). The 110 genes in PI3K/AKT/mTOR pathway are often mutated in luminal BC. The most common *PI3K* mutations are found in around 40% of cases in luminal subtypes [26].

The alpha catalytic subunit of PI3K (PIK3CA) has been identified as the site of the bulk of *PI3K* mutations in ER-positive tumors. The most prevalent somatic mutation in BC is *PIK3CA*, which is seen in 36% of individuals with hormone receptor-positive, HER2-negative (HR+/HER2−) BC [27]. Crosstalk between the ER and the PI3K/AKT/ mTOR signaling pathways has been proposed to be present during BC progression. Estrogens activate the PI3K/AKT/mTOR pathway, which allows ER cancers to migrate and invade distant tissues. mTOR signaling regulates the expression and activity of ER-α (one of two isoforms) in a reciprocal manner [8]. A recent study suggests that inhibition of the PI3K pathway activated the histone-lysine N-methyltransferase 2D (KMTD2), resulting in ER activation in BC cells [28]. Importantly, when AKT/mTOR signaling is activated by PI3K antagonists, the activation of energy-active mitochondria to the cortical cytoskeleton of cancer cells occurs. In this way, tumor cell invasion is increased. Inhibitors of the PI3K pathway slow cancer development, however, they

may promote tumor invasion by reprogramming mitochondrial transport, OXPHOS, and boosting cell motility [29].

ER-positive tumors exhibit lower levels of glycine, lactate, and glutamate (high glutamine), as well as reduced glutaminolysis. Therefore, this suggests that ER is involved in tumor metabolic control. Through interaction with many important regulators and pathways, including PI3K/AKT/mTOR, TP53, c-MYC, and Ras/Raf/ MAPK, ER plays a crucial role in metabolic control, allowing tumors to reprogram their metabolism to match diverse sorts of environments [29]. By activating ER-α, 17b-estradiol can increase insulin receptor expression while lowering the lipogenic activity of lipoprotein lipase in adipose tissue. Furthermore, Estradiol (E2) and ER-α can both control how the metabolism is reprogrammed in the presence of glucose. E2 promotes glycolysis by upregulating AKT kinase activity and inhibits TCA cycle activity in high glucose situations. On the other hand, in low glucose conditions, E2 activates the TCA cycle by upregulating PDH activity and suppresses glycolysis to meet the tumor cell's energy needs [30]. Importantly, recent research revealed that E2 appeared to promote glycolysis whereas tamoxifen inhibited it. E2 can upregulate *GLUT1* transcriptionally and so enhance glycolysis [31]. The other form of ER is ER-b. In high-grade BC, ER-b expression is downregulated or absent. ER-b, like ER-α, appears to boost glycolysis while suppressing OXPHOS in glucose metabolism. Multiple glycolysis-related pathways are elevated in ER-b-activated mammospheres, suggesting that ER-b plays a major role in regulating BC stem cell metabolism [32]. Epigenetic alterations are mostly enzymatic and possibly reversible. Methylation of DNA, acetylation of histone proteins, and changes in miRNA expression are all epigenetic alterations that affect protein synthesis patterns [33].

In mammalian cells, DNA methylation is one of the essential epigenetic changes. While it controls gene expression in normal development and growth, it is dysregulated in cancer. DNA methyltransferases (DNMTs) such as DNMT1, DNMT3a, and DNMT3b catalyze the methylation of CpG islands in DNA. DNMT1 is critical for methylation to be maintained during DNA replication in normal cells during mitosis. Its absence can result in hypomethylation. *De novo* methylation patterns are thought to be generated by DNMT3a and DNMT3b. DNMT1, DNMT3a, and DNMT3b expression levels are higher in BC than in normal breast tissue. When compared to DNMT1 and DNMT3a, the DNMT3b gene has the largest range of expression [34]. This suggests that DNTM3b is the primary actor in BC. Studies have shown that there are nearly 70% of methylated-CpG islands in the human genome and are found in closely packed core regions of DNA, where they affect gene silence and chromosomal integrity.

On contrary, unmethylated CpG islands are present in relaxed, the open state typically promoter regions of DNA. In this way, transcription factors and other regulatory proteins can access housekeeping and regulatory genes for expression. Normal cells are transcriptionally active. Because CpG islands that are present in the promoters of tumor-suppressor genes are frequently unmethylated in normal cells. On the other hand, in malignant tumors, hypermethylation of CpG islands that are found in promoters of tumor-suppressor genes is observed. Several studies have found and analyzed DNA methylation patterns and their association with breast cancer development and progression throughout the last decade. Cell cycle regulation (Ras Association Domain Family Member 1 -*RASSF1A*), Cyclin-Dependent Kinase Inhibitor 2A (*CDKN2A*), Cyclin-Dependent Kinase Inhibitor 1B (*CDKN1B*), Cyclin D2 (*CCND2*), DNA repair *(*BRCA1 DNA Repair Associated-*BRCA1*), MutL homolog 1 (*MLH1*), O-6-Methylguanine-DNA Methyltransferase (*MGMT*), cell
