FABP7 is a key metabolic regulator in HER2+ breast cancer brain metastasis

Cordero, Álex; Kanojia, Deepak; Miska, Jason; Panek, Wojciech K.; Xiao, Annie; Han, Yu; Bonamici, Nicolas; Zhou, Weidong; Xiao, Ting; Wu, Meijing; Ahmed, Atique U.; Lesniak, Maciej S.

doi:10.1038/s41388-019-0893-4

Cited by 66 publications

(52 citation statements)

References 74 publications

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“…Moreover, the richness of fatty acids per se that are generally elevated in obesity in the microenvironment may contribute to tumour development 35,37 . Fatty acid-binding proteins (FABPs) that function to solubilise various FAs and coordinate their trafficking inside the cells 47,48 are recently reported as a new linkage between obesity and breast cancer [49][50][51][52] . After entry into cancer cells, exogenous fatty acids cannot only serve as efficient energy-producing nutrients but also act as secondary signalling messengers to coordinate signal transduction cascades that modulate carcinogenic processes 6 .…”

Section: Discussionmentioning

confidence: 99%

Proto-oncogene Src links lipogenesis via lipin-1 to breast cancer malignancy

Song

Liu

et al. 2020

Nat Commun

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Increased lipogenesis has been linked to an increased cancer risk and poor prognosis; however, the underlying mechanisms remain obscure. Here we show that phosphatidic acid phosphatase (PAP) lipin-1, which generates diglyceride precursors necessary for the synthesis of glycerolipids, interacts with and is a direct substrate of the Src proto-oncogenic tyrosine kinase. Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride. Alteration of the three tyrosine residues to phenylalanine (3YF-lipin-1) disables lipin-1 from mediating Src-enhanced glycerolipid synthesis, cell proliferation and xenograft growth. Re-expression of 3YF-lipin-1 in PyVT;Lpin1−/− mice fails to promote progression and metastasis of mammary tumours. Human breast tumours exhibit increased p-Tyr-lipin-1 levels compared to the adjacent tissues. Importantly, statistical analyses show that levels of p-Tyr-lipin-1 correlate with tumour sizes, lymph node metastasis, time to recurrence and survival of the patients. These results illustrate a direct lipogenesis-promoting role of the pro-oncogenic Src, providing a mechanistic link between obesity-associated mitogenic signaling and breast cancer malignancy.

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Section: Discussionmentioning

confidence: 99%

Proto-oncogene Src links lipogenesis via lipin-1 to breast cancer malignancy

Song

Liu

et al. 2020

Nat Commun

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“…Cells expressing reporters may activate immune response in HER2+ cells and in BrM 43. FABP7 is thought to induce a more glycolytic, metastatic, and pro-angiogenic state in BC cells, thereby enhancing the survival of HER2+ BC in the foreign brain microenvironment 43. Thus, beyond just HER2 expression and its interaction with other receptors, other aspects of HER2+ BC biology likely contribute to the brain metastatic potential of this subtype.…”

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confidence: 99%

HER2‐positive breast cancer brain metastasis: A new and exciting landscape

Zimmer

Swearingen²,

Anders³

2020

Cancer Reports

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Background: Brain metastases (BrM) incidence is 25% to 50% in women with advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Radiation and surgery are currently the main local treatment approaches for central nervous system (CNS) metastases. Systemic anti-HER2 therapy following a diagnosis of BrM improves outcomes. Previous preclinical data has helped elucidate HER2 brain trophism, the blood-brain/blood-tumor barrier(s), and the brain tumor microenvironment, all of which can lead to development of novel therapeutic options. Recent findings: Several anti-HER2 agents are currently available and reviewed here, some of which have recently shown promising effects in BrM patients, specifically. New strategies driven by and focusing on brain metastasis-specific genomics, immunotherapy, and preventive strategies have shown promising results and are under development. Conclusions: The field of HER2+ breast cancer, particularly for BrM, continues to evolve as new therapeutic strategies show promising results in recent clinical trials. Increasing inclusion of patients with BrM in clinical studies, and a focus on assessing their outcomes both intracranially and extracranially, is changing the landscape for patients with HER2+ CNS metastases by demonstrating the ability of newer agents to improve outcomes.

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“…Many studies have relied on BT-474 and MDA-MB-361 cells for brain metastasis models of HER2-positive breast cancer [21][22][23]. However, no studies in breast cancer brain metastasis have used multiple cell lines and compared gene expression or proliferative ability among them.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, some cell lines derived from primary sites have the potential to metastasize to other organs. For example, breast cancer cell lines BT-474 and HCC-1954 cells are sampled from the mammary gland, but they can survive in the brain [21][22][23]. Thus, it is important to reclassify the metastatic activities of cancer cell lines by transplantation models.…”

Section: Introductionmentioning

confidence: 99%

Proliferative Classification of Intracranially Injected HER2-positive Breast Cancer Cell Lines

Kuroiwa

Nakayama

Adachi

et al. 2020

Cancers

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HER2 is overexpressed in 25–30% of breast cancers, and approximately 30% of HER2-positive breast cancers metastasize to the brain. Although the incidence of brain metastasis in HER2-positive breast cancer is high, previous studies have been mainly based on cell lines of the triple-negative subtype, and the molecular mechanisms of brain metastasis in HER2-positive breast cancer are unclear. In the present study, we performed intracranial injection using nine HER2-positive breast cancer cell lines to evaluate their proliferative activity in brain tissue. Our results show that UACC-893 and MDA-MB-453 cells rapidly proliferated in the brain parenchyma, while the other seven cell lines moderately or slowly proliferated. Among these nine cell lines, the proliferative activity in brain tissue was not correlated with either the HER2 level or the HER2 phosphorylation status. To extract signature genes associated with brain colonization, we conducted microarray analysis and found that these two cell lines shared 138 gene expression patterns. Moreover, some of these genes were correlated with poor prognosis in HER2-positive breast cancer patients. Our findings might be helpful for further studying brain metastasis in HER2-positive breast cancer.

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FABP7 is a key metabolic regulator in HER2+ breast cancer brain metastasis

Cited by 66 publications

References 74 publications

Proto-oncogene Src links lipogenesis via lipin-1 to breast cancer malignancy

Proto-oncogene Src links lipogenesis via lipin-1 to breast cancer malignancy

HER2‐positive breast cancer brain metastasis: A new and exciting landscape

Proliferative Classification of Intracranially Injected HER2-positive Breast Cancer Cell Lines

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