Amino Acids Breast Cancer Diagnosis and Treatment: History
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Contributor:
Lyudmila V. Bel’skaya
,
Ivan A. Gundyrev
,
Denis V. Solomatin

It was shown that the content of individual amino acids changes in breast cancer by an average of 10–15% compared with healthy controls. For some amino acids (Thr, Arg, Met, and Ser), an increase in concentration is more often observed in breast cancer, and for others, a decrease is observed (Asp, Pro, Trp, and His). The accuracy of diagnostics using individual amino acids is low and increases when a number of amino acids are combined with each other or with other metabolites. Gln/Glu, Asp, Arg, Leu/Ile, Lys, and Orn have the greatest significance in assessing the risk of breast cancer.

  • amino acids
  • breast cancer
  • diagnosis
  • imaging
  • risk
  • prognosis
  • treatment

1. Introduction

Breast cancer (BC) remains the leading malignant neoplasm in women and the second leading cause of death from cancer among women worldwide [1][2]. Treatment for breast cancer has improved in recent years, but its high mortality remains a concern. Existing treatments for breast cancer often lead to intractable drug resistance. Therefore, the need for methods of early diagnosis and the identification of risk factors and groups are still relevant tasks. To solve these problems, scientists began to study the metabolic pathway in breast cancer. The connection between breast cancer and metabolic pathways may also lead to the discovery of new therapeutic possibilities and targets [3][4].
Recently, much attention has been paid to metabolomics as an effective tool for differentiating samples from patients with breast cancer from normal samples [5][6][7][8][9][10][11]. For example, a statistically significant difference in 24 metabolites in breast cancer compared with the control group was found by Dougan et al. [12], and a statistically significant difference in 78 metabolites was confirmed by Shen et al. [8]. Interestingly, the levels of metabolites are unique for different types of cancer, which could be a new way to classify tumors [13]. Jobard et al. identified nine metabolites to differentiate between metastatic and early breast cancer, although a separation of breast cancer phenotypes based on metabolomics is still controversial [14][15]. Several metabolomic studies of plasma/serum breast cancer have been performed, mainly aimed at distinguishing between the subtypes of breast cancer [16], metastatic breast cancer [8][14][17][18][19][20], recurrence [21][22], response to neoadjuvant chemotherapy [23][24], etc. An important part of the metabolomic profile, which makes it possible to discriminate between BC patients and healthy controls, is represented by amino acids. Amino acids in breast cancer are determined in the tissue [25][26][27], serum [7][28][29][30], plasma [6][31][32][33][34], saliva [35][36][37][38], and urine [39][40][41]. Amino acids not only play a vital role in the synthesis of biological molecules such as proteins in malignant cancer cells, but they are also important metabolites for immune cell activation and antitumor activity in the tumor microenvironment. Abnormal changes in the amino acid metabolism are closely associated with the onset and development of tumors and immunity [42]. An amino acid can supply sources of nitrogen and carbon for biosynthesis or satisfy the energy requirement for the rapid growth of tumor cells [43].

2. Diagnostic Value of Determination of Amino Acids in Biological Fluids

2.1. Amino Acid Composition of Serum and Blood Plasma in Breast Cancer

In different studies, both the contents of individual amino acids and the complete amino acid profile of plasma and/or serum were evaluated. It has been shown, for example, that the arginine levels were significantly lower and the ornithine levels were significantly higher in breast cancer patients than in control patients [44]. Differences between breast cancer cases and controls were observed for the levels of Trp, Thr, Ala, Gly, Pro, Ile, Leu, and Val [34]. Miyagi et al. observed significant changes in the amino acid profiles between cancer patients and controls. They found that the concentrations of Thr, Pro, Ser, Gly, Ala, and Orn were significantly higher, but the concentrations of Gln, Trp, His, Phe, and Tyr were significantly lower compared to the control. Compared with the data from Lai et al., they found similarities in decreasing His and Gln levels and increasing Pro and Ala levels in breast cancer patients. Budczies et al. demonstrated that changes in the amino acid metabolism were associated with at least a 1.9-fold increase in 16 amino acids in breast cancer compared with healthy breast tissue [45][46]. 

To compare the change in the contents of individual amino acids in breast cancer according to different authors, scholars compared the relative contents of amino acids in relation to healthy controls. It can be seen that a significant change in the concentration is rarely observed, for example, an increase in the contents of Arg [47][48], Thr [47], and Ser [33] by 2 times, a decrease in the content of Asp by 1.5 times [48][49], etc. In most cases, the change in concentration is up to 10–15% compared to the control.
It can be seen that for some amino acids (Thr, Arg, Met, and Ser), an increase in concentration is more often observed in breast cancer compared with a healthy control, and for other amino acids, a decrease is observed (Asp, Pro, Trp, and His). However, in each case, to assess the change in the amino acid profile, it is necessary to take into account the characteristics of the sample due to the high heterogeneity of breast cancer.

2.2. Features of the Amino Acid Composition of Serum/Plasma in Different Molecular Biological Subtypes of Breast Cancer

In a number of studies, special attention was paid to the influence of the molecular biological characteristics of breast cancer on the amino acid profile of blood serum/plasma. Thus, Ala had a significant difference between ER-positive and ER-negative breast cancer [16][50]. Fan Y. identified a panel of eight potential low-molecular-weight biomarkers for diagnosing breast cancer subtypes, which included three amino acids: Pro, Ala, and Val [16]. Elevated Pro levels (FC = 1.217, p = 0.007) may indicate the suppression of proline oxidase in the human growth factor receptor 2 (HER2) positive group [51]. Ala was the most significantly reduced metabolite (FC = 0.544, p < 0.001) in the ER-positive participants compared to the ER-negative group [50]. Val was significantly increased in the HER2-positive groups compared to the HER2-negative groups, but was markedly decreased in the ER-positive groups compared to the ER-negative groups. Val anomalies indicated a violation of energy supply in the HER2-positive (fold change = 1.187, p = 0.002) and ER-positive (fold change = 0.682, p < 0.001) patients. The authors emphasized the clinical predictive potential of the identified eight biomarkers for breast cancer subtypes. An average prediction accuracy of 88.5% (95% CI 83.3–93.7%) was obtained for the training set and an average prediction accuracy of 85.6% (95% CI 80.9–90.1%) was obtained for the test set.

2.3. Racial Characteristics of the Serum/Plasma Amino Acid Profile in Breast Cancer

Breast cancer is associated with marked metabolic changes. However, these metabolic shifts in tumors may differ between stages, subtypes, and race [8][52]. Racial differences may not only influence metabolite levels, but also modify associations between metabolites and breast cancer. Racial differences in the incidence of breast cancer are well documented [53][54][55]. Compared to Caucasian American (CA) women, African American (AA) women tend to develop more aggressive tumors that are characterized by an earlier age at diagnosis, a higher mitotic index, and a lower prevalence of ER/PR expression, and subsequently have a lower survival rate. It has been suggested that genetic predisposition plays a role in racial/ethnic disparity in breast cancer [56][57].
Amino acids are most often positively associated with breast cancer risk, and among them are the branched-chain amino acids Val and Leu, as well as Lys, Arg, Phe, and Gln [58]. They are also positively associated with the risk of His as a necessary precursor of histamine, the release of which is an early event in inflammatory responses and is a regulator of cell proliferation [59].
The branched-chain amino acids (BCAAs) Leu, Val, and Ile are dietary essential amino acids and are important metabolites that are involved in cell signaling pathways and muscle protein synthesis [60]. Elevated plasma BCAA concentrations are strongly positively correlated with body mass index and insulin resistance and are markers of a dysfunctional metabolism [61]. In premenopause, elevated levels of circulating BCAAs have been associated with a lower risk of breast cancer [61]. In contrast, among postmenopausal women, elevated levels of circulating BCAAs have been associated with an increased risk of breast cancer [62].
The AminoIndex Cancer Screening (AICS) technology has been described and used as a new cancer risk calculation method for early cancer diagnosis [34][63][64][65][66]. AICS (breast) detects breast cancer by detecting abnormal plasma concentrations of Thr, Ala, Orn, His, and Trp [67]. In breast cancer, the Thr, Ala, and Orn concentrations are elevated, while the His and Trp concentrations are reduced, and a multivariate analysis shows an overall accuracy of 88.2% [68].
Thus, it was shown that the risk of breast cancer is associated with the amino acid composition of blood plasma/serum; however, the patterns identified by the authors are closely related to the characteristics of the sample, menopausal status, and age. Nevertheless, according to most authors, Gln/Glu, Asp, Arg, Leu/Ile, Lys, and Orn have the greatest significance in assessing the risk of breast cancer.

3. Amino Acid Metabolism in Breast Cancer

3.1. Metabolic Features of Breast Cancer

The amino acid metabolism plays a critical role in the proliferation of breast cancer cells [69][70]. The intake and use of amino acids helps to support the growth of cancer cells [71][72][73]. A number of studies have shown that a decrease in the content of a number of amino acids may be the result of their excessive consumption or preferential use to support the uncontrolled growth of breast cancer cells [5][26][37][72][73][74][75].
The Glu/Gln, Ala, Asp, and Arg metabolisms were the most important biosynthetic pathways in breast cancer, suggesting extensive metabolic disturbances during breast cancer progression [76][77]. Huang S. et al. showed that the alanine, aspartate, and glutamate pathways are critical biological pathways for the early diagnosis of breast cancer [30]. Most of the metabolites in these three metabolic pathways were reduced in breast cancer patients compared to healthy controls. Thus, Ala promotes the proliferation of breast cancer cells, which indicates the potential role of Ala as a marker for cancer diagnosis [47]. The down-regulation of Gln indicated that Glu can accumulate in the body, which contributes to the development of breast cancer due to the increased proliferation of mammary epithelial cells [78] due to ATP production and nucleotide biosynthesis [79]. Moreover, Glu activation via glutaminolysis can maintain the citric acid cycle [80]. The metabolism of Gln is closely related to the process of providing energy to the cancer cell. Gln is transported into cancer cells by means of multiple transporters [77][81]. It was previously shown that the expressions of the Gln transporters ASCT2, SNAT1, SNAT2, and SNAT5 are increased in tumor tissue [82]. On the other hand, the inhibition of ASCT2 reduces the growth of TNBC [83]. It is known that the reductive metabolism of Gln supports tumor growth under conditions of hypoxia, mitochondrial dysfunction [84], and in an environment with a low nutrient content [85]. It was noted that Gln/Glu reversibility decreased in MCF-7 cells, indicating that breast cancer cells may be partially associated with irreversible glutaminase [86]. The Gln/Glu ratio can be used as a biomarker for the diagnosis of breast cancer [87]. The enzyme glutaminase I (GLS-I), which converts Gln to Glu via glutaminolysis, can be considered as a target for breast cancer therapy [88].
The change in the Gln level can be reflected in fluctuating levels of Ala and Asp due to the abnormal transport of ammonia. Higher histidine decarboxylase activity may lead to a decrease in the His levels [89], and low concentrations of His may be associated with increases in Asp and Glu, which can be converted to oxaloacetic and α-ketoglutaric acids, which are intermediates of the tricarboxylic acid cycle. Asp has been shown to be more sensitive to breast cancer [90]. Therefore, an increase in the use of Asp by BC cells can lead to a decrease in the levels of Asp and oxaloacetate in the blood. 
The dysregulation of branched-chain amino acid (BCAA) metabolism, including Leu, Ile, and Val, has been reported to be associated with specific cancer phenotypes. BCAAs can inhibit tumor growth and metastasis [91], so changes in the BCAA levels can often reflect systemic changes in cancer patients compared to healthy controls [92]. Plasma Arg, Pro, and Trp metabolites decreased in BC patients [6]. 

3.2. Amino Acid Metabolism as a Target for Breast Cancer Imaging

Elevated levels of Met, Gln, Cys, Trp, Tyr, and other amino acids in tissues have been noted in many malignancies, including breast cancer [93]. Cancer cells with the up-regulation of amino acid metabolism stimulate the increased transport of amino acids into the cell [94]. The increased consumption of amino acids and the overexpression of amino acid transporters in malignant tumors make radiolabeled amino acids attractive imaging agents [75][95].
Multiple amino acid transporters have been demonstrated to be up-regulated in breast cancer families, including L-type amino acid transporter (LAT1), ASC transporter 2 (ASCT2), ATB0,+, SNAT1, and xc- [96][97]. LAT1 is required for the transport of large neutral amino acids and is overexpressed in many types of malignancies, including breast cancer [98]. The expression of ASCT2 also has prognostic associations in breast cancer [81]. The xc-system transporter, which mediates cysteine uptake, is up-regulated in some breast cancer tumors [99]. The two amino acid transporters SLC7A5 and SLC7A11 are considered essential for the growth of breast cancer cells in a cell-dependent manner [100].
Met is a naturally occurring large neutral amino acid that is readily labeled with the 11C radioactive isotope. 11C-methionine serves as a metabolic marker for Met uptake via L-type amino acid transporters. PET with 11C-methionine makes it possible to visualize primary and metastatic lesions, as well as to predict the response to breast cancer treatment [101]. Limitations of 11C-methionine include the ability to detect metastases only in the liver and bone marrow and its relatively short half-life (20 min). On the basis of Met, an MR contrast agent based on Met-MSN-Gd3+ was developed that targets methionine receptors, which are overexpressed in tumor cells (MSN—Mesoporous Silica Nanoparticles) [102][103].
Trans-1-amino-3-18F-fluorocyclobutanecarboxylic acid (anti-18F-FACBC, also known as 18F-fluciclovine) is a synthetic analogue of Leu, which is transported into the cell by the ASCT2 transporter with the additional involvement of LAT1 [104]. Uptake by cells is most similar to uptake of the natural amino acid Gln [105]. 18F-fluciclovine can visualize breast lesions [106][107], axillary lymph node metastases [108], and previously undetected extra-axillary nodular metastases [108][109]. Preclinical studies have demonstrated significant success with 18F-fluciclovine in detecting bone metastases.
(4S)-4-(3-[18F]fluoropropyl)-l-glutamate (BAY 94-9392, also known as [18F]FSPG), is a synthetic amino acid analogue of SLC7A11 [99][110]. Histological or molecular subtypes of breast cancer may affect 18F-FSPG uptake. 18F-5-fluoroaminosuberic acid, a synthetic amino acid substrate of SLC7A11, exhibited tumor uptake in three breast cancer cell lines (MDA-MB-231, MCF-7, and ZR-75-1), with the highest uptake observed in MDA-MB- 231, the TNBC cell line [111].

4. Amino Acids in Potential Strategies for the Treatment of Breast Cancer

Some essential amino acids (EAAs)—Trp, His, Met, and branched-chain amino acids—are directly associated with tumor growth and treatment resistance [112][113][114][115]. EAAs provide important raw materials for protein synthesis, influence the biological behavior of cells, and induce therapeutic resistance in breast cancer cells. Strekalova et al. [116] found that Met plays a critical role in maintaining the self-renewal and survival of cancer stem cells. Met restriction reduced the population of cancer stem cells in TNBC. Saito et al. [117] showed that Leu not only promotes cell proliferation in ER-positive breast cancer, but also participates in the mechanism of resistance to tamoxifen. In addition, essential amino acids, as important nutrients, mediate the development of an immunosuppressive tumor microenvironment in breast cancer. For example, kynurenine, a product of Trp metabolism, can inhibit T cell proliferation and differentiation, leading to immune evasion and tumor progression in breast cancer [118]. Interestingly, both Trp and kynurenine were lower in plasma in breast cancer patients compared to controls, especially in women with estrogen-receptor-negative and advanced breast cancers [119]. These results show an intrinsic relationship between EAA metabolism and the immune microenvironment in breast cancer.

Under physiological conditions, Gln is transported into cells by many transporters such as Ala, Ser, Cys-preferential transporter 2 (ASCT2, also known as SLC1A5), and L-type amino acid transporter 1 (LAT1, also known as SLC7A5). In TNBC, both ASCT2 and LAT1 are overexpressed [83][120]. Compared to other subtypes of breast cancer, TNBC is more Gln dependent and sensitive to glutaminolysis-targeted therapy due to glutaminase overexpression (GLS) [121][122], which is associated with high-grade metastatic breast cancer. Several small-molecule GLS inhibitors, such as CB-839, have been developed to combat the dysregulation of glutaminolysis [123]. Other combination therapies, such as the combination of GLS inhibition and bevacizumab (an anti-angiogenesis monoclonal antibody targeting VEGF), also show antitumor effects on TNBC [124]. Ginsenoside was described to effectively inhibit TNBC by suppressing Gln uptake and Glu production by down-regulating glutaminase 1 (GLS1) expression [125]. Ginsenoside treatment further reduced cellular ATP production, decreased amino acid utilization associated with Gln metabolism, and induced glutathione depletion and reactive oxygen species accumulation, which consequently triggered apoptosis in TNBC. 

Increased Glu production by GLS may support the uptake of exogenous cystine via the cystine/glutamate antiporter xCT to maintain redox balance. As a clinically approved anti-inflammatory drug, sulfasalazine (SASP) was found to inhibit xCT activity and retard the growth of TNBC [126]. By immunizing mice with a DNA-based vaccine expressing the xCT protein, the cell surface immunotargeting of the xCT antigen effectively attenuated tumor growth and lung metastasis, and increased chemosensitivity to doxorubicin [127]. 

In addition to Gln and Cys, TNBC cells are also somewhat dependent on the availability of several other amino acids such as Met, Asp, and Arg, suggesting that restricting these amino acids may have a therapeutic effect [128]. The depletion of either Met or Gln can increase the cell surface expression of the pro-apoptotic TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) and increase the sensitivity of TNBC cells to TRAIL-induced apoptosis [129][130]. Met deprivation in the diet increases cellular susceptibility to lexatumumab, an agonistic monoclonal antibody targeting TRAIL-R2, and reduces the rate of lung metastasis [131]. In addition, many tumor and stem cells depend on the biosynthesis of the universal methyl donor S-adenosylmethionine from the exogenous Met via methionine adenosyltransferase 2α (MAT2A) to maintain their epigenome [132][133]. A restriction on Met is enough to undermine the ability of TNBC to initiate a tumor, which is in part due to the impaired formation of S-adenosylmethionine. The combination of methionine restriction and the MAT2A inhibitor cycloleucine has a synergistic antitumor effect [116]. Under normal physiological conditions, the serum levels of Asp are lower than in the mammary gland, making Asp bioavailability a key regulator of circulating tumor cells and the metastatic potential of breast cancer. The restriction of Asp intake by the suppression of asparagine synthetase, treatment with L-asparaginase, or the restriction of Asp intake in the diet inhibits breast cancer metastasis [130]. The depletion of Arg by recombinant human arginase (rhArg) leads to the apoptosis of TNBC cells via reactive oxygen species and induces adaptive autophagy, while blocking the flow of autophagy via autophagy-targeting drugs enhances rhArg cytotoxicity [134]. The deprivation of Arg by L-arginase impairs tumor growth, leading to cell death [135]. Much attention has been paid to epigenetic modifications caused by enzymes of protein arginine methyltransferases, in which methylate Arg make a great contribution to the process of breast carcinogenesis and tumor suppression [136] and are targets for many types of cancer [137].

Leu uptake is predominantly mediated by the L-type amino acid transporter (LAT) family, a group of four Na+-independent transporters (LAT1, SLC7A5; LAT2, SLC7A8; LAT3, SLC43A1; and LAT4, SLC43A2) with an affinity for branched and neutral amino acid transporters [129]. Glutamine transport is largely mediated by Ala, Ser, and Cys-preferential transporter 2 (ASCT2; SLC1A5). 

Amino acid deprivation (AADT) is becoming a promising strategy for the development of new therapeutic agents against cancer [138]. The rapid growth of tumors leads to a decrease in the expression of certain enzymes, which leads to the auxotrophy of some specific amino acids. Amino acid depletion selectively inhibits tumor growth because normal cells can synthesize amino acids through their normal machinery. The enzymes used in AADT are primarily obtained from microbes due to their easy availability. Thus, the deprivation of Gln leads to a decrease in cell proliferation and cell death in breast cancer cell lines [139].
Endocrine therapy is the standard treatment for estrogen-receptor-positive (ER+) breast cancer, but 40% of women experience a recurrence of the disease during therapy. A general analysis of transcription in cells revealed a suppression of the neutral and basic amino acid transporter SLC6A14, which is regulated by the increased expression of miR-23b-3p, which leads to impaired amino acid metabolism [140]. This altered cellular amino acid metabolism is supported by autophagy activation and the increased import of acidic amino acids (Asp and Glu) mediated by the SLC1A2 transporter. Targeting these amino acid metabolic dependencies increases the sensitivity of cells to endocrine therapy.
The use of various drugs based on platinum nanoparticles leads to a disruption of the amino acid metabolism, a disruption of tRNA aminoacylation, and protein synthesis [141]. Mitrevska et al. [142] analyzed the effect on amino acid metabolism in MDA-MB-231 cells upon treatment with cisplatin, PtNP-10, and PtNP-40, and revealed a marked contrast between the effects of cisplatin and PtNP. The results indicate a higher sensitivity of MDA-MB-231 cells to PtNP compared to cisplatin, since the increase in the number of amino acids was associated with the degree of insensitivity to various chemotherapeutic agents [142].
In general, combinations of anticancer drugs and amino acids can improve the intratumoral distribution of the active substance and increase its bioavailability. In particular, amino acid-based poly(ether urea ester) (AA-PEUU), as a nanocarrier for the systemic delivery of gamboginic acid, demonstrates the effectiveness of engineered AA-PEUU nanocarriers with custom structures and universal customization for the systemic delivery of therapeutics in the treatment of TNBC [143].
Plasma amino acid analysis can be used to monitor treatment progress. So, Minet-Quinard et al. [144] showed that the plasma levels of Ser and Glu returned to normal six months after the surgical removal of the tumor. Dunstan et al. [145] considered the changes in the amino acid homeostasis during radiation therapy. The urinary histidine and alanine levels were shown to be elevated prior to radiotherapy, while the Thr, Met, Ala, Ser, Asp, and Gln levels were higher after 5 weeks of radiotherapy. Many complications such as cachexia, anorexia, and fatigue occur in the treatment of problems associated with breast cancer, and many studies have considered the addition of amino acids with BCAAs [146] or a single amino acid or its derivative [147] to reduce the effects of treatment.

This entry is adapted from the peer-reviewed paper 10.3390/cimb45090474

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