Genome-wide screen identifies a novel prognostic signature for breast cancer survival

Mao, Xuan; Lee, Matthew J.; Zhu, Jeffrey; Zhu, Carissa; Law, Sindy; Snijders, Antoine M.

doi:10.18632/oncotarget.14776

Cited by 19 publications

(17 citation statements)

References 59 publications

(53 reference statements)

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“…4). LPAR6 is highly expressed in the liver and HCC (12,42) and has been shown to support liver tumorigenesis (42). LPAR6 is also the highest expressing LPAR in the lung (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

The Autotaxin—Lysophosphatidic Acid Axis Promotes Lung Carcinogenesis

et al. 2018

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Pathogenesis and progression of lung cancer are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epigenetic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor-like phospholipid that is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotropic effects in almost all cell types are mediated through at least six G-protein coupled LPA receptors (LPAR) that exhibit overlapping specificities, widespread distribution, and differential expression profiles. Here we use both preclinical models of lung cancer and clinical samples (from patients and healthy controls) to investigate the expression levels, activity, and biological role of the above components of the ATX/LPA axis in lung cancer. was genetically altered in 8% of patients with lung cancer, whereas increased ATX staining and activity were detected in patient biopsies and sera, respectively. Moreover, expression was consistently downregulated in patients with lung cancer. Comparable observations were made in the two most widely used animal models of lung cancer, the carcinogen urethane-induced and the genetically engineered -driven models, where genetic deletion of or resulted in disease attenuation, thus confirming a procarcinogenic role of LPA signaling in the lung. Expression profiling data analysis suggested that metabolic rewiring may be implicated in the procarcinogenic effects of the ATX/LPA axis in- -driven lung cancer pathogenesis. These findings establish the role of ATX/LPA in lung carcinogenesis, thus expanding the mechanistic links between pulmonary fibrosis and cancer. .

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Section: Discussionmentioning

confidence: 99%

The Autotaxin—Lysophosphatidic Acid Axis Promotes Lung Carcinogenesis

et al. 2018

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“…This contributes to the increase in LPA concentrations in the tumors [110][111][112]. Low LPP1 mRNA expression (PLPP1) is one of 12 changes in mRNA that predicts poor survival in breast cancer patients [113]. We showed that increasing the low levels of LPP1 in breast cancer cells decreases cell division and blocks tumor growth and metastases in a mouse breast cancer model bỹ 80% [27].…”

Section: Effects Of Lpp Expression In Cancersmentioning

confidence: 95%

Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

Benesch

Tang

Brindley

2020

Cancers

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After a decade of intense preclinical investigations, the first in-class autotaxin inhibitor, GLPG1690, has entered Phase III clinical trials for idiopathic pulmonary fibrosis. In the intervening time, a deeper understanding of the role of the autotaxin–lysophosphatidate (LPA)–lipid phosphate phosphatase axis in breast cancer progression and treatment resistance has emerged. Concordantly, appreciation of the tumor microenvironment and chronic inflammation in cancer biology has matured. The role of LPA as a central mediator behind these concepts has been exemplified within the breast cancer field. In this review, we will summarize current challenges in breast cancer therapy and delineate how blocking LPA signaling could provide novel adjuvant therapeutic options for overcoming therapy resistance and adverse side effects, including radiation-induced fibrosis. The advent of autotaxin inhibitors in clinical practice could herald their applications as adjuvant therapies to improve the therapeutic indexes of existing treatments for breast and other cancers.

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“…The expressions of these two LPPs are decreased in lung, ovarian, and breast tumors [ 97 , 98 , 99 ] and this can contribute to the increase of LPA concentrations in the tumors [ 100 , 101 , 102 ]. Low expression of mRNA for LPP1 is one of 12 changes in mRNA that predicts poor survival in breast cancer patients [ 103 ]. We showed that mRNA concentrations for LPP1 were lower in all types of breast tumors compared to normal breast tissue [ 27 , 51 ].…”

Section: Role Of Lipid Phosphate Phosphatases In Controlling Lpa Smentioning

confidence: 99%

Role of Adipose Tissue-Derived Autotaxin, Lysophosphatidate Signaling, and Inflammation in the Progression and Treatment of Breast Cancer

Brindley

Tang

Meng

et al. 2020

IJMS

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Autotaxin (ATX) is a secreted enzyme that produces lysophosphatidate (LPA), which signals through six G-protein coupled receptors, promoting tumor growth, metastasis, and survival from chemotherapy and radiotherapy. Many cancer cells produce ATX, but breast cancer cells express little ATX. In breast tumors, ATX is produced by tumor-associated stroma. Breast tumors are also surrounded by adipose tissue, which is a major bodily source of ATX. In mice, a high-fat diet increases adipocyte ATX production. ATX production in obesity is also increased because of low-level inflammation in the expanded adipose tissue. This increased ATX secretion and consequent LPA signaling is associated with decreased adiponectin production, which results in adverse metabolic profiles and glucose homeostasis. Increased ATX production by inflamed adipose tissue may explain the obesity-breast cancer association. Breast tumors produce inflammatory mediators that stimulate ATX transcription in tumor-adjacent adipose tissue. This drives a feedforward inflammatory cycle since increased LPA signaling increases production of more inflammatory mediators and cyclooxygenase-2. Inhibiting ATX activity, which has implications in breast cancer adjuvant treatments, attenuates this cycle. Targeting ATX activity and LPA signaling may potentially increase chemotherapy and radiotherapy efficacy, and decrease radiation-induced fibrosis morbidity independently of breast cancer type because most ATX is not derived from breast cancer cells.

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Genome-wide screen identifies a novel prognostic signature for breast cancer survival

Cited by 19 publications

References 59 publications

The Autotaxin—Lysophosphatidic Acid Axis Promotes Lung Carcinogenesis

The Autotaxin—Lysophosphatidic Acid Axis Promotes Lung Carcinogenesis

Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

Role of Adipose Tissue-Derived Autotaxin, Lysophosphatidate Signaling, and Inflammation in the Progression and Treatment of Breast Cancer

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