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FATTY ACID SYNTHESIS IS REQUIRED FOR BREAST CANCER BRAIN METASTASIS.

ABSTRACT: Brain metastases are refractory to therapies that control systemic disease in patients with human epidermal growth factor receptor 2 (HER2+) breast cancer, and the brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for brain metastatic breast cancer growth may introduce liabilities that can be exploited for therapy. Here, we assessed how metabolism differs between breast tumors in brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in brain. We determine that this phenotype is an adaptation to decreased lipid availability in brain relative to other tissues, resulting in a site-specific dependency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase (FASN) reduces HER2+ breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies.

SUBMITTER: Ferraro GB

PROVIDER: S-EPMC8223728 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTandem C2 domains, nuclear (TC2N) is a C2 domain-containing protein that belongs to the carboxyl-terminal type (C-type) tandem C2 protein family, and acts as an oncogenic driver in several cancers. Previously, we preliminarily reported that TC2N mediates the PI3K-Akt signaling pathway to inhibit tumor growth of breast cancer (BC) cells. Beyond that, its precise biological functions and detailed molecular mechanisms in BC development and progression are not fully understood.MethodsTumor tissues of 212 BC patients were subjected to tissue microarray and further assessed the associations of TC2N expression with pathological parameters and FASN expression. The protein levels of TC2N and FASN in cell lines and tumor specimens were monitored by qRT-PCR, WB, immunofluorescence and immunohistochemistry. In vitro cell assays, in vivo nude mice model was used to assess the effect of TC2N ectopic expression on tumor metastasis and stemness of breast cancer cells. The downstream signaling pathway or target molecule of TC2N was mined using a combination of transcriptomics, proteomics and lipidomics, and the underlying mechanism was explored by WB and co-IP assays.ResultsHere, we found that the expression of TC2N remarkedly silenced in metastatic and poorly differentiated tumors. Function-wide, TC2N strongly inhibits tumor metastasis and stem-like properties of BC via inhibition of fatty acid synthesis. Mechanism-wise, TC2N blocks neddylated PTEN-mediated FASN stabilization by a dual mechanism. The C2B domain is crucial for nuclear localization of TC2N, further consolidating the TRIM21-mediated ubiquitylation and degradation of FASN by competing with neddylated PTEN for binding to FASN in nucleus. On the other hand, cytoplasmic TC2N interacts with import proteins, thereby restraining nuclear import of PTEN to decrease neddylated PTEN level.ConclusionsAltogether, we demonstrate a previously unidentified role and mechanism of TC2N in regulation of lipid metabolism and PTEN neddylation, providing a potential therapeutic target for anti-cancer.

Project description:Breast cancer is the most common malignancy among women worldwide, and the main cause of death in patients with breast cancer is metastasis. Metastasis to the central nervous system occurs in 10% to 16% of patients with metastatic breast cancer, and this rate has increased because of recent advancements in systemic chemotherapy. Because of the various treatments available for brain metastasis, accurate diagnosis and evaluation for treatment are important. Magnetic resonance imaging (MRI) is one of the most reliable preoperative examinations not only for diagnosis of metastatic brain tumors but also for estimation of the molecular characteristics of the tumor based on radiographic information such as the number of lesions, solid or ring enhancement, and cyst formation. Surgical resection continues to play an important role in patients with a limited number of brain metastases and a relatively good performance status. A single brain metastasis is a good indication for surgical treatment followed by radiation therapy to obtain longer survival. Surgical removal is also considered for two or more lesions if neurological symptoms are caused by brain lesions of >3 cm with a mass effect or associated hydrocephalus. Although maximal safe resection with minimal morbidity is ideal in the surgical treatment of brain tumors, supramarginal resection can be achieved in select cases. With respect to the resection technique, en bloc resection is generally recommended to avoid leptomeningeal dissemination induced by piecemeal resection. An operating microscope, neuronavigation, and intraoperative neurophysiological monitoring are essential in modern neurosurgical procedures, including tumor resection. More recently, supporting surgical instruments have been introduced. The use of endoscopic surgery has dramatically increased, especially for intraventricular lesions and in transsphenoidal surgery. An exoscope helps neurosurgeons to comfortably operate regardless of patient positioning or anatomy. A tubular retractor can prevent damage to the surrounding brain tissue during surgery and is a useful instrument in combination with both an endoscope and exoscope. Additionally, 5-aminolevulinic acid (5-ALA) is a promising reagent for photodynamic detection of residual tumor tissue. In the near future, novel treatment options such as high-intensity focused ultrasound (HIFU), laser interstitial thermal therapy (LITT), oncolytic virus therapy, and gene therapy will be introduced.

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FATTY ACID SYNTHESIS IS REQUIRED FOR BREAST CANCER BRAIN METASTASIS.

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