Breast cancer is the leading cause of death in women worldwide (Sung et al., 2021). Breast cancer varies based on the presence of receptors such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) (Al-Thoubaity, 2020, Harbeck et al., 2019, Luond et al., 2021). The basal-like subtype, also known as triple-negative breast cancer (TNBC), is characterized by triple negativity for ER, PR, and HER2 and is observed in approximately 15–20 % of breast cancer patients (Al-Thoubaity, 2020). TNBC is highly aggressive, with distant metastasis, ineffective chemotherapy, and a high risk of relapse (Yin et al., 2020).
Cancer cells tend to increase their glucose uptake and prefer glycolysis instead of oxidative phosphorylation for glucose metabolism and this is also known as the Warburg effect (Liberti and Locasale, 2016). TNBC exhibits metabolic changes with increased glucose metabolism and dependence (Wang et al., 2020b), underscoring the feasibility of targeting glucose utilization. Glucose transporter 1 (GLUT1) that is essential for glucose metabolism, proliferation, and invasion of cancer cells is often upregulated in TNBC cells (Oh et al., 2017, Sun et al., 2020). Several amino acid transporters are upregulated in TNBC cells (Cha et al., 2018). Solute carrier family 7 member 11 (SLC7A11; xCT) is abundantly expressed in breast cancer cells (Jyotsana et al., 2022, Lin et al., 2020, Tang et al., 2022). xCT, a functional subunit of the cystine/glutamate transporter, is responsible for pumping out intracellular glutamate and for the uptake of cystine (Lo et al., 2008) that is essential for maintaining the redox balance (Koppula et al., 2021). However, several studies revealed that glucose depletion upregulates SLC7A11 expression and disrupts oxidative stress homeostasis in breast cancer cells (Jyotsana et al., 2022, Shin et al., 2017). Variations in SLC7A11 expression in different breast cancer cells may contribute to varying degrees of glucose dependence (Chen et al., 2020).
The eukaryotic translation initiation factor-2α (eIF2α)-activating transcription factor-4 (ATF4) integrated stress response (ISR) is a pathway that helps eukaryotic cells adapt to stress such as external environmental (hypoxia, viral infections, and amino acid or glucose deficiencies) and endogenous (unfolded proteins in the endoplasmic reticulum stress) stress (Pakos-Zebrucka et al., 2016). The ISR pathway is crucial for cancer cells to adapt to environmental stress and affects cancer development and progression (Licari et al., 2021, Tian et al., 2021, Wang et al., 2020a). During glucose starvation, ATF4 increases SLC7A11 expression, leading to glucose and glutamine dependence in cancer cells (Koppula et al., 2017, Koppula et al., 2018, Shin et al., 2017). A glucose-deficient environment increases the levels of reactive oxidative species (ROS) in breast cancer cells and induces SLC7A11 expression, thereby regulating glucose dependence (Chen et al., 2020, Chen et al., 2021).
TNBC cells require more glutamine than do other breast cancer cell subtypes (Timmerman et al., 2013, Yang et al., 2017). Recent studies have identified 14 glutamine transporters on the cell membrane, with solute carrier family 1 member 5 [SLC1A5, also called alanine/serine/cysteine transporter 2 (ASCT2)] being the most researched. SLC1A5 is highly expressed in TNBC cell lines and regulates glutamine uptake and cell growth (van Geldermalsen et al., 2016). A recent study discovered that a variant of the SLC1A5 gene, known as SLC1A5var, is responsible for transporting glutamine into the mitochondria and increasing glutamine metabolism in cancer cells when glucose is limited (Yoo et al., 2020). SLC1A5 possesses eight exons and several transcript variants, including SLC1A5 (GenBank: NM_005628.2) that lacks the second exon and encodes 541 amino acids and SLC1A5var (GenBank: NM_001145145.1) that lacks the first exon, encodes 339 amino acids, and possesses a mitochondrial-targeting sequence (Scalise et al., 2018, Yoo et al., 2020). SLC1A5var is critical for metabolic changes in cancer cells, including promotion of mitochondrial respiration and glycolysis. Compared to SLC1A5, SLC1A5var exerts a more substantial effect on mitochondrial glutamine metabolism and cancer cell proliferation (Yoo et al., 2020). SLC1A5var is highly expressed in breast cancer, and higher expression levels are associated with lower overall survival rates in breast cancer patients (Yoo et al., 2020). Additionally, the expression of SLC1A5var affects drug resistance (Yoo et al., 2020). Thus, mitochondrial SLC1A5var has been proposed to play a role in the glucose dependence of cancer cells. However, it remains unclear if SLC1A5var is involved in ISR-induced glucose dependence. We hypothesized that cancer cells activate ISR in the absence of glucose, resulting in increased expression of mitochondrial SLC1A5var that regulates the glucose dependence of cancer cells. SLC1A5var may be a potential target for cancer treatment and acts at a crucial crossroads in metabolic reprogramming.