Expression of Adipocyte/Macrophage Fatty Acid–Binding Protein in Tumor-Associated Macrophages Promotes Breast Cancer Progression

Hao, Jiaqing; Yan, Fei; Zhang, Kun; Triplett, Ashley; Zhang, Ying; Schultz, Debra A.; Sun, Yanwen; Zeng, Jun; Silverstein, Kevin A.T.; Zheng, Qi; Bernlohr, David A.; Cleary, Margot P.; Egilmez, Nejat K.; Sauter, Edward R.; Liu, Shujun; Suttles, Jill; Li, Bing

doi:10.1158/0008-5472.can-17-2465

Cited by 117 publications

(88 citation statements)

References 48 publications

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“…Chemotherapy, the sole therapeutic route for TNBC patients, causes severe toxicity, resistance, and relapse; therefore, a better understanding of TNBC biology is needed. Mechanistic studies show strong links between adiposity, fatty acid metabolism, and BC risk [2][3][4][5], establishing a rationale for exploring related networks such as TNBC targets. Interest in the potential of the fatty acid binding protein (FABP) family, in particular, has recently been gaining traction.…”

Section: Introductionmentioning

confidence: 99%

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Deregulating the CYP2C19/Epoxy-Eicosatrienoic Acid-Associated FABP4/FABP5 Signaling Network as a Therapeutic Approach for Metastatic Triple-Negative Breast Cancer

Apaya

Hsiao

Yang

et al. 2020

Cancers

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Recurrence and metastasis are the main causes of triple-negative breast cancer (TNBC) mortality. On the basis of our clinical cohorts and integrative omics analyses, we hypothesized that understanding the interplay between fatty acid binding protein (FABP) and epoxy-eicosatrienoic acid (EET) driven metastatic progression can uncover a new opportunity for TNBC intervention. In this study, the biological relevance of increased protein expression of CYP2C19, FABP4, and FABP5 in TNBC tumors and in the TNBC cell line (MDA-MB-231), as well as its highly metastatic lung seeking variant (LM6) were delineated from publicly available datasets, shRNA-mediated knockdown, EET supplementation, cancer and stromal cell co-cultures, and an orthotopic and resection xenograft tumor mouse model. We found that the high expression levels of CYP2C19 and FABP4 and FABP5 are critical in TNBC metastatic transformation and stromal cell interactions. Furthermore, EET-associated nuclear translocation of FABP4 and FABP5 and nuclear accumulation of SREBP-2 or PPAR-γ influence TNBC cell proliferation, migratory transformation, and distal metastasis priming. Most notably, we uncovered novel bioefficacy and modes of action of the anticancer drug doxorubicin and a phytogalactolipid, 1,2-di-O-α-linolenoyl-3-O-β-galactopyranosyl-sn-glycerol (dLGG), which effectively attenuated TNBC recurrence and lung metastasis through deregulating the FABP/EET dynamics and levels. This study, therefore, introduces a novel approach to combating TNBC by targeting the FABP/EET/CYP-associated metastatic signaling network.

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Section: Introductionmentioning

confidence: 99%

“…They activate transcription factors that are associated with proliferation, differentiation, and vascularization in multiple cancer types [8][9][10]. They may also act as mediators of cancer cell-stromal interactions [3,11,12].…”

Section: Introductionmentioning

confidence: 99%

Deregulating the CYP2C19/Epoxy-Eicosatrienoic Acid-Associated FABP4/FABP5 Signaling Network as a Therapeutic Approach for Metastatic Triple-Negative Breast Cancer

Apaya

Hsiao

Yang

et al. 2020

Cancers

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“…Emerging evidence suggested that FABPs were associated with the development and progression of cancers [9][10][11]. A FABP inhibitor, BMS309403, was used to investigate if it could generate a similar effect to that seen in the berberinetreated cells.…”

Section: E Fabp Inhibitor Bms309403 Could Partially Recapitulate Thmentioning

confidence: 99%

“…FABPs, members of the superfamily of lipid-binding proteins, are key lipid metabolic enzymes responsible for the regulation of fatty acid uptake and intracellular transport [8]. It was reported that FABPs were closely associated with cancer development and were upregulated in many cancers such as renal cell carcinoma [9], hepatocellular carcinoma [10], and breast cancer [11], which indicates the potential role of FABPs as the tumor markers and therapeutic targets in some cases.…”

Section: Introductionmentioning

confidence: 99%

Berberine Suppressed Tumor Growth through Regulating Fatty Acid Metabolism and Triggering Cell Apoptosis via Targeting FABPs

Peng

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Aim. To further investigate the mechanism behind the antitumor properties of berberine regarding lipid metabolism. Methods. Cell viability, proliferation, and apoptosis assays were performed to determine the antigrowth effects of berberine in vitro. Ectopic xenograft models in Balb/c nude mice were established to determine the antitumor effects of berberine in vivo. Results. Berberine inhibited cell viability and proliferation of MGC803 human gastric cancer cell lines in a time-and dose-dependent manner. Berberine induced apoptosis of MGC803 and increased the apoptotic rate with higher doses. Berberine induced the accumulation of fatty acid of MGC803 and suppressed the protein expression of FABPs and PPARα. e FABP inhibitor BMS309403 recapitulated the effects of berberine on MGC803 cells. In the xenograft model, berberine significantly decreased the tumor volume and tumor weight and induced apoptosis in tumor tissues. Berberine significantly elevated the fatty acid content and inhibited the expression of FABPs and PPARα in the MGC803 xenograft models. Conclusion. Berberine exerted anticancer effects on human gastric cancer both in vitro and in vivo by inducing apoptosis, which was due to the reduced protein expression of FABPs and the accumulation of fatty acid.

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“…For example, A-FABP (also known as FABP4) is predominantly expressed in adipose tissue while epidermal FABP (E-FABP, FABP5) is the major FABP in the epidermis [3][4][5]. Our recent studies demonstrate that A-FABP expression in macrophages promotes protumour functions of tumour associated macrophages (TAM) in mouse models of breast cancer (BC) [6,7]. Moreover, A-FABP is secreted by adipose tissue to promote obesity-associated BC [8].…”

Section: Introductionmentioning

confidence: 99%

A-FABP and oestrogens are independently involved in the development of breast cancer

Hao

Yan

et al. 2019

Adipocyte

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We previously reported that postmenopausal obese women exhibit increased levels of circulating adipocyte fatty acid binding protein (A-FABP), which is associated with breast cancer (BC) development. In postmenopause, increased oestrogen levels are reported to be associated with increased BC risk. Herein, we assessed if oestrogens, including oestrone (E1), oestradiol (E2) and oestriol (E3), are associated with A-FABP in the obesity-related BC development. We collected 249 serum samples from women with or without BC and measured serum levels of E1, E2, E3 and A-FABP. Considering all subjects, E1 and E2 but not E3 levels were significantly higher in pre-than in postmenopause individuals. E3 and E1 levels were higher in non-obese than in obese women. When samples were separated by BC status, E2 levels were significantly higher, while E1 and E3 levels were significantly lower in postmenopausal obese than non-obese women without BC. These differences based on body mass index (BMI) were not observed among women with BC. E3 levels were higher in obese women with BC than those without. A-FABP levels were significantly higher in postmenopausal obese women regardless of BC status. In addition, A-FABP was not associated with E1, E2 or E3. Altogether, our data suggest that A-FABP is independently regulated by obesity and menopausal status compared to oestrogens, thus playing a unique role in the development of BC. ARTICLE HISTORY

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Expression of Adipocyte/Macrophage Fatty Acid–Binding Protein in Tumor-Associated Macrophages Promotes Breast Cancer Progression

Cited by 117 publications

References 48 publications

Deregulating the CYP2C19/Epoxy-Eicosatrienoic Acid-Associated FABP4/FABP5 Signaling Network as a Therapeutic Approach for Metastatic Triple-Negative Breast Cancer

Deregulating the CYP2C19/Epoxy-Eicosatrienoic Acid-Associated FABP4/FABP5 Signaling Network as a Therapeutic Approach for Metastatic Triple-Negative Breast Cancer

Berberine Suppressed Tumor Growth through Regulating Fatty Acid Metabolism and Triggering Cell Apoptosis via Targeting FABPs

A-FABP and oestrogens are independently involved in the development of breast cancer

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