Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

Benesch, Matthew G.K.; Tang, Xiaoyun; Brindley, David N.

doi:10.3390/cancers12020374

Cited by 31 publications

(67 citation statements)

References 140 publications

(218 reference statements)

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“…One of the important functions of ATX and LPA signaling is in wound healing. ATX is secreted by activated platelets and secretion from tissues is increased by inflammation that is caused by tissue damage or infections [ 29 , 30 ]. The consequent increase in LPA signaling stimulates wound repair by activating the migration and division of fibroblasts and keratinocytes in the wounded area [ 31 ] and by facilitating collagen deposition [ 32 ], which leads to the formation of scar tissue.…”

Section: Role Of Atx Activity In Wound Healing Chronic Inflammatimentioning

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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Section: Role Of Atx Activity In Wound Healing Chronic Inflammatimentioning

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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“…Notably, breast cancer cells produce very little ATX [27][28][29]. Instead, ATX is secreted by breast adipocytes and this activity increases in response to inflammation caused by cytokines produced by an adjacent breast tumor [30][31][32][33]. The resulting LPA is then able to activate LPA receptor-mediated signaling in the tumor cells.…”

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confidence: 99%

“…The anti-inflammatory effects of glucocorticoids depend on: (a) binding of glucocorticoid receptors to glucocorticoid-responsive elements, which modify gene expression by inducing the expression of annexin I and MAPK phosphatase-1); (b) indirect effects on gene expression through the interactions of glucocorticoid receptors with transcription factors, including NFκB and activator protein 1; and (c) glucocorticoid receptor-mediated effects on second-messenger cascades including the PI3K-Akt-eNOS pathway [42]. These effects decrease the production of pro-inflammatory eicosanoids and cytokines, which would contribute to the observed attenuation of the activity of the ATX-LPA inflammatory cycle [33].Based on the established ability of DEX to attenuate RT-induced inflammation of lung tissue [43-45] and lung fibrosis [45,46] and on our recent observation [41] that DEX suppresses ATX-LPA-LPA 1 receptor signaling in cultured breast adipose tissue, we hypothesized that inhibiting the activation of the ATX-LPA-inflammatory cycle would attenuate the subsequent development of fibrosis in the…”

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confidence: 99%

mentioning

confidence: 99%

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Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast Fibrosis

Meng

Wuest

Tang

et al. 2020

Cancers

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We recently showed that radiation-induced DNA damage in breast adipose tissue increases autotaxin secretion, production of lysophosphatidate (LPA) and expression of LPA1/2 receptors. We also established that dexamethasone decreases autotaxin production and LPA signaling in non-irradiated adipose tissue. In the present study, we showed that dexamethasone attenuated the radiation-induced increases in autotaxin activity and the concentrations of inflammatory mediators in cultured human adipose tissue. We also exposed a breast fat pad in mice to three daily 7.5 Gy fractions of X-rays. Dexamethasone attenuated radiation-induced increases in autotaxin activity in plasma and mammary adipose tissue and LPA1 receptor levels in adipose tissue after 48 h. DEX treatment during five daily fractions of 7.5 Gy attenuated fibrosis by ~70% in the mammary fat pad and underlying lungs at 7 weeks after radiotherapy. This was accompanied by decreases in CXCL2, active TGF-β1, CTGF and Nrf2 at 7 weeks in adipose tissue of dexamethasone-treated mice. Autotaxin was located at the sites of fibrosis in breast tissue and in the underlying lungs. Consequently, our work supports the premise that increased autotaxin production and lysophosphatidate signaling contribute to radiotherapy-induced breast fibrosis and that dexamethasone attenuated the development of fibrosis in part by blocking this process.

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“…Additionally, cancer stem cells (CSCs) are intrinsically resistant to chemotherapy due to their pluripotent and dormant state [3]. CSCs survive through most treatments, mutating to give rise to a more aggressive, resistant phenotype, contributing to metastatic disease, and is prevalent in TNBC [4].…”

Section: Introductionmentioning

confidence: 99%

Next-Generation Multimodality of Nanomedicine Therapy: Folic Acid Conjugated Copolymer and Folate Receptor Interactions Disrupt Receptor Functionality Resulting in Dual Therapeutic Anti-Cancer Potential in Triple-Negative Breast Cancer

DeCarlo¹,

Malardier-Jugroot²,

Szewczuk³

2020

Preprint

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The development of a highly specific drug delivery system (DDS) for anti-cancer therapeutics is an area of intense research focus. Chemical engineering of a “smart” DDS to specifically target tumor cells has gained interest, designed for safer, more efficient, and effective use of chemotherapeutics for the treatment of cancer. However, the selective targeting and choosing the critical cancer surface biomarker are essential for targeted treatments to work. The folic acid receptor alpha (FRalpha) has gained popularity as a potential target in triple-negative breast cancer (TNBC). We have previously reported on a functionalized folic acid (FA)-conjugated amphiphilic alternating copolymer poly(styrene-alt-maleic anhydride) (FA-DABA-SMA) via a biodegradable linker 2,4-diaminobutyric acid (DABA) that has the essential features for efficient “smart” DDS. This biocompatible DDS self-assembles in a pH-dependent manner, providing stimuli-responsive, active targeting, extended-release of hydrophobic chemotherapeutic agents, and can effectively penetrate the inner core of 3-dimensional cancer spheroid models. The empty FA-DABA-SMA decreased spheroid volume, revealing a previously unknown mechanism of action. Upon further investigation, a size- and shape-dependent interaction FA-DABA-SMA with FR reduced the expression of p53, the product of the highly mutated TP53 gene, and additional oncogenic c-Myc and STAT3 proteins. Here, we investigated how this copolymer influences FR behavior and disrupting the receptor’s functions. Results indicate that FA-DABA-SMA increases FR expression levels in breast MDA MB-231 cancer cells and disrupting FR signaling by the reduction in HES1 and NOTCH1 protein expression levels. Also, FA-DABA-SMA induces apoptosis and further causes a change in the morphology of the MDA MB-231 cells, as well as significantly reduces their ability to migrate in a Scratch wound assay. Collectively, these findings provide a novel insight into the functionalized FA-DABA-SMA copolymer. The 350 kDa and 20 kDa copolymers actively target FRα to initialize internationalization. However, only the large size and sheet-shaped 350 kDa copolymers disrupt FRα signaling. The significance of these novel findings reveals the intracellular activity of the copolymer that is critically dependent on the size and structural shape. This report offers novel therapeutic insight into a dual mechanism of FA-DABA-SMA copolymer for its therapeutic potential for the treatment of cancer.

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Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

Cited by 31 publications

References 140 publications

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

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

Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast Fibrosis

Next-Generation Multimodality of Nanomedicine Therapy: Folic Acid Conjugated Copolymer and Folate Receptor Interactions Disrupt Receptor Functionality Resulting in Dual Therapeutic Anti-Cancer Potential in Triple-Negative Breast Cancer

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