• Targeted triple-negative breast cancer therapies are needed • Interfering with phospholipid metabolism inhibits tumor • Lipidomics revealed the mechanism behind the breast cancer lipid metabolism target
OF all breast cancer patients, 10 to 20 % are diagnosed with triple-negative breast cancer (TNBC). TNBC is a type of breast cancer that is more likely to be found in people younger than age 50, it is more aggressive, and has poorer prognosis than other types of breast cancer.
The growth of triple-negative breast cancer is not fueled by estrogen, progesterone, or the HER2 protein. Thus, it does not respond to hormonal therapies based on estrogen or progesterone receptors or medications targeting the HER2 protein receptors – it is triple negative.
Though other medicines exist, new therapeutic approaches for TNBC are required to improve treatment quality. Targeting lipid metabolism, specifically phospholipid metabolism, is a promising research subject in oncology. For example, inhibiting cardiolipin biosynthesis has been shown to impact growth of hypoxic cancers. With lipid analysis, metabolic aberrations in tumors can be discovered to develop new treatment opportunities.
Cancers require lipids such as phospholipids and fatty acids for increased membrane biogenesis to proliferate rapidly. They reprogram their metabolism to increase synthesis of macromolecules. But, cancer cells need not to synthesize fatty acids on their own, they can harvest them from their microenvironment. This strategy leaves little room for targeting fatty acid biosynthesis successfully in tumor therapy. However, this does not apply to phospholipid metabolism in breast cancer initiation and progression.
Phospholipids are important components of biological membranes. They are lipids which contain a phosphate group in their head. The phosphate group can be linked to further molecules, like choline in phosphatidylcholine or ethanolamine in phosphatidylethanolamine. If no further molecules are linked to the phosphate group, the phospholipid is a phosphatidate.
General pathway for phospholipid synthesis: The biochemical pathways of phospholipid synthesis in mammalian cells. The enzyme lipin-1 is highlighted. He et al., FASEB Journal (2017), doi: 10.1096/fj.201601353R
The biosynthesis of the different phospholipid classes is deeply interwoven. Many of these processes take place in the endoplasmic reticulum (ER). A critical and rate-limiting step in phospholipid metabolism is the removal of the phosphate group from phosphatidate, which is facilitated by the enzyme lipin-1. The product of this conversion is diacylglycerol, to which phosphorylated choline or ethanolamine can then be attached to form phosphatidylcholine and phosphatidylethanolamine.
LPIN1, the gene encoding the enzyme lipin-1, is significantly upregulated in triple negative breast cancer, and the overexpression of LPIN1 correlates highly with poor patient survival. Researchers from the University of Texas Health Science Center at Houston down-regulated lipin-1 production in TNBC cells to investigate the role of the enzyme in breast cancer phospholipid metabolism.
LPIN1 expression in TNBC:A Comparison of the LPIN1 gene readout levels in TNBC and non-TNBC breast cancers. B High LPIN1 gene readout correlates with shorter overall survival of patients with TNBC. He et al., FASEB Journal (2017), doi: 10.1096/fj.201601353R
They applied lipidomics, expecting that the inhibition of lipin‐1‐mediated phospholipid metabolism on the ER would lead to unbalanced production of phospholipids. Indeed, in TNBC cells with down-regulated lipin-1, the composition of phospholipid classes was altered with consistent changes in fatty acid length among all major phospholipid classes.
However, dysregulation of phospholipid metabolism in the ER can lead to ER stress, a condition that disrupts the endoplasmic reticulum in its vital role in protein folding. This leads to the accumulation of misfolded or unfolded proteins, proteins that are not biologically functional or even harmful to the cell.
Phospholipid composition of TNBC cells: Changes in lipid species that may be directly regulated by lipin‐1 activity. Only the top 15 most abundant species of each phospholipid class are presented. He et al., FASEB Journal (2017), doi: 10.1096/fj.201601353R
The unfolded protein response (UPR) evolved to protect the cell from ER stress. Upon activation, the UPR aims to restore normal cell function by pausing protein synthesis, degrading misfolded proteins, and activating processes to support protein folding. If these goals are not achieved within a certain time span, the ER stress triggers apoptosis, programmed cell death.
From ER stress to apoptosis: Phospholipid metabolism aberrations in the Endoplasmic Reticulum (ER) activates the IRE1α pathway, and thus the Unfolded Protein Response (UPR). If the ER stress persists the UPR remains activated. This initiates apoptosis, programmed cell death.
The down-regulation of lipin-1 led to dysregulation of phospholipid metabolism in the ER of TNBC cells, thus constantly activating the IRE1α signaling pathway and the UPR. Ultimately, the prolonged ER stress resulted in apoptosis and death of the TNBC cells.
This effect was confirmed in a mouse model, showing that lipin-1 is critical to maintain ER homeostasis and thus tumor growth in TNBC – even in vivo. This demonstrates that targeting phospholipid metabolism may be a therapeutic strategy for treating patients with TNBC, and also other cancers.
Triple-negative breast cancer is typically treated with a combination of surgery, radiation therapy, and chemotherapy. Yet, hurdles such as chemotherapy insensitivity, incomplete surgical removal, and further success-limiting factors continue to stir an intense interest in finding new medications and treatment methods for triple-negative breast cancer from academia to industry.
Lipidomics helps proving that targeting phospholipid metabolism may be a therapeutic strategy for treating patients with TNBC and other cancers. Lipotype Lipidomics provides the tools to investigate cancer lipid metabolism.
As a comprehensive health science university, the mission of The University of Texas Health Science Center at Houston is to educate health science professionals, discover and translate advances in the biomedical and social sciences, and model the best practices in clinical care and public health.
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