**2. Mechanism of metastasis in breast cancer subtypes**

BC is a very common cancer type that can arise either genetically or environmentally. It is divided into different subtypes according to its genetic overcomes (**Figure 1**). Each subtype has its specific genomic character. Therefore, their inner signaling pathways' roles in metastasis are quite distinct.

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

#### **Figure 1.**

*Breast cancer is heterogenous cancer that includes 4 major subtypes according to their mutations. Estrogen receptors (ER) and progesterone (PR) receptors are specialized proteins found in certain cells in the body. Estrogen, progesterone, and female hormones circulating in the blood bind to these receptors and promote new cell growth and division. HER2 is a growth-promoting protein found outside of all breast cells (−, no expression; +, high expression).*

#### **2.1 Luminal A and B**

ER-positive BC is divided into two types: luminal A and luminal B. It is shown to have different gene expression patterns, prognoses, and therapeutic responses. When compared to luminal A tumors, luminal B tumors have lower levels of ER or estrogenregulated genes, lower or no expression of the PR higher tumor grade, higher expression of proliferation-related genes, and activation of growth factor receptor signaling pathways like IGF-1R and PI3K/AKT/mTOR [2]. Luminal B cancers, like luminal A tumors, are expected to have reduced endocrine sensitivity but have increased chemotherapy sensitivity [3].

Extravasation or lymphatic, local invasion, intravasation, colonization, and blood vessel migration are all steps in the tumor metastasis process. These processes then lead to metastases to distant organs [4]. The connection between tumor cells and the tumor microenvironment, which includes noncancerous cells such as immune cells, fibroblasts, adipocytes, and endothelial cells and as well as extracellular matrix (ECM), is crucial for organ-specific colonization [5]. The parallel progression model is more prevalent in breast tumors than the linear metastasis model. This suggests that BC cells spread early in the tumor's formation and that cancer cell spread may not be

dependent on tumor progression [6]. Several investigations have demonstrated that the genetic modifications of BC bone metastasis cells are not necessarily the same as those of their primary tumors. Distinct BC subtypes have been demonstrated to favor different metastatic sites, which are influenced by different molecular pathways. The molecular characteristics of BC and target organs appear to validate the organotropism of metastasis. All BC subtypes are prone to bone metastasis when compared to other subtypes; however, the luminal A subtype is an extraordinarily high-risk factor for bone metastasis. In addition, the prevalence of bone metastasis in luminal subtype malignancies is significantly higher (80.5%) than in HER2+ tumors (55.6%) or basallike tumors (41.7%) [7]. Not only proliferation and metastatic capacities of BC subtypes are different, but also metabolic genotypes and phenotypes, vary with subtype. Nonetheless, metabolic alterations may differ not just within BC subtypes, but also depending on how tumor cells interact with their microenvironment [8]. This section highlights current knowledge about the association between metabolic programming, epigenetic modifications, and the metastatic process in BC. Understanding the metabolic processes that induce BC spread may lead to the development of new anticancer drugs.

Normal cells engage several signaling pathways in response to external growth signals and regulate glycolysis, oxidative phosphorylation (OXPHOS), and anabolic metabolism. Furthermore, unlike normal cells, which make adenosine triphosphate (ATP) largely by OXPHOS via the TCA cycle, most cancer cells rely on glycolysis for energy during aerobic conditions. The reverse Warburg effect, also known as metabolic coupling, is a metabolism that some tumor cells have. This mechanism not only results in chemotherapy resistance but also explains why some tumor cells have a high rate of mitochondrial respiration but a low rate of glycolysis [9, 10]. Moreover, the research identified a link between the luminal subtype and metabolically inactive reverse-Warburg/null phenotypes, whereas triple-negative breast cancer (TNBC) was linked to metabolically active Warburg/mixed phenotypes [11].

The expression of glucose transporter proteins (GLUTs) varies in BC and is connected to different clinical phases. In BC cells, GLUT1-5 and GLUT12 are active, although GLUT1 is the most important [12]. The pentose phosphate pathway (PPP) produces fructose-6-phosphate, nicotinamide adenine dinucleotide phosphate (NADPH), and ribose phosphate in addition to glycolysis and the TCA cycle [13]. Proteins involved in PPP are expressed in diverse ways in different molecular subtypes of BC. For instance, the HER2 subtype has greater expression of 6-phosphogluconolactonase and glucose-6-phosphate dehydrogenase than other BC subtypes, indicating a more active PPP [14]. Transketolase and G6PD expression have been associated with a worse overall and relapse-free survival rate in BC patients [15].

Glutathione and nicotinamide adenine dinucleotide (NADH) are the intermediates of glutamine and aid tumor cell proliferation and development by providing energy, supplementing glucose metabolism, and helping cells survive oxidative stress. Furthermore, certain tumor cells have developed an "addiction to glutamine", meaning that when there is no glutamine, they cannot survive [16]. Oncogenic transcription factors c-MYC and RAS can raise the metabolic activity of glutamine in tumor cells. At the same time, they can also upregulate some glutamine transporters including alanine-serine-cysteine transporter 2 (ASCT2) and enzymes involved in glutamine-to-glutamate conversion like glutaminase (GLS-1) [17]. Recent studies revealed that a greater glutamate-to-glutamine ratio particularly in ER-negative tumors was observed in breast tumor tissues. Glutaminase-1 (*GLS-1*), glutamate dehydrogenase (*GDH*), and *ASCT2* were found to be more strongly expressed in
