David Brindley

David Brindley


Ph.D, D.Sc., University of Birmingham

Office: 780-492-2078
Lab: 780-492-4613
Fax: 780-492-3383


Our work focuses on understanding how changes in signal transduction increased the growth of breast tumours, their spread (metastasis) and the development of therapy resistance. We concentrate on the enzyme, autotaxin (ATX), which is an important component in promoting wound healing(1). This is because ATX produces a compound called lysophosphatidate (LPA), which activates six G-protein coupled receptors. Signalling by extracellular LPA is terminated by a family of enzymes called lipid phosphate phosphatases (LPPs)(2). LPP1 and LPP3 activities are decreased in breast tumours. Increasing LPP1 expression decreases LPA signalling, tumor growth and metastasis(3). Conversely, LPP2 activity is increased in breast tumours leading to increased cell division and tumour growth(4).

LPA receptors normally stimulate the migration, proliferation and survival of cells during wound healing and they increase the development of a new blood supply(1). These functions of ATX and LPA are hijacked by tumours, which are likened to "wounds that do not heal". We showed that LPA signalling is part of a feedforward cycle of inflammation in breast cancer where the tumours secrete inflammatory cytokines, which stimulate ATX transcription and secretion by surrounding cells. The LPA, which is formed by ATX, then stimulates the secretion of more inflammatory cytokines. Thus, inhibiting ATX activity decreases the production of >20 inflammatory cytokines and chemokines and this decreases tumour growth and metastasis(5). Equally, the ATX-LPA-inflammatory cycle can be inhibited by targeting inflammation e.g., with an inhibitor of TNF-α action, Infliximab, which diminishes ATX-LPA signalling and blocks the metastasis of breast tumours by ~60%(6).

One of the effects of chronic tumour-induced inflammation is to enable cancer cells to avoid destruction by the immune system. Thus, we showed that blocking ATX-LPA signalling increases the numbers of CD8+-T cells in breast tumours, which will potentially improve immune-surveillance(7).

We also discovered that LPA decreases the effectiveness of taxanes(8), doxorubicin(9) and tamoxifen(10), which are used to treat breast cancer. This is partly because LPA signalling increases the stability of the transcription factor, Nrf2. This activates the anti-oxidant response element, which increases the expression of proteins that protect cancer cells from oxidative damage caused by chemotherapeutic agents. In addition, Nrf2 increases the transcription of the multidrug resistance transporters, which export toxic oxidation products and chemotherapeutic drugs from cancer cells(9). Nrf2 also increases the transcription of enzymes involved in DNA repair(1), which protects against the beneficial effects of chemotherapy and radiotherapy (RT). This explains why inhibiting ATX improves the effectiveness of RT in killing breast cancer cells(11).

RT is used to treat the majority of cancers but one of its significant side-effects is to produce scarring (fibrosis). This is promoted by ATX and activation of LPA1 receptors. We are presently studying breast cancer patients undergoing RT to determine if the magnitude and/or the duration of the ATX-LPA-inflammatory response to RT is prognostic for the early development of RT-induced fibrosis.

Another focus of our work is the role of infection with cytomegalovirus (CMV), which affects 40-70% of Canadian women with breast cancers. We showed that being seropositive for CMV, or having gB DNA-positive tumours, was associated with 5.6-times more likelihood of developing Stage IV cancers with reduced relapse-free survival(12). Also, CMV infection of mice with breast cancer was associated with increased metastasis(13). Our working hypothesis is that these effects of CMV involve activation of the ATX-LPA-inflammatory cycle.

Our work is designed to support the introduction of agents that can decrease the effect of ATX-LPA-inflammatory signalling to provide a new approach to improving the treatment of cancers. This work can be translated into clinical practice using ATX inhibitors that have entered clinical trials.

Selected Publications:

1.Signalling by lysophosphatidate and its health implications.
Hemmings DG and Brindley DN.
Essays Biochem (2020) 64, 547-563.

2. Lipid Phosphate Phosphatases and Cancer.
Tang X and Brindley DN.
Biomolecules (2020) 10.

3. Increasing the low lipid phosphate phosphatase 1 activity in breast cancer cells decreases transcription by AP-1 and expressions of matrix metalloproteinases and cyclin D1/D3.
Tang X, McMullen TP, Brindley DN.
Theranostics (2019) 9, 6129-6142

4. Lipid phosphate phosphatase-2 promotes tumor growth through increased c-Myc expression.
Tang X, Cromwell CR, Liu R, Godbout R, Hubbard BP, McMullen TP, Brindley DN.
Theranostics (2022) 12, 5675-5690.

5. Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression.
Benesch MG, Tang X, Dewald J, Dong WF, Mackey JR, Hemmings DG, McMullen TP, Brindley DN.
FASEB J. (2015) 29, 3990-4000

6. Infliximab, a Monoclonal Antibody against TNF-alpha, Inhibits NF-kappaB Activation, Autotaxin Expression and Breast Cancer Metastasis to Lungs.
Shinde A, Tang X, Singh R, Brindley DN.
Cancers (Basel) (2023) 16

7. Autotaxin Inhibition with IOA-289 Decreases Breast Tumor Growth in Mice Whereas Knockout of Autotaxin in Adipocytes Does Not.
Tang X, Morris AJ, Deken MA, Brindley DN
Cancers (Basel) (2023) 15.

8. Autotaxin protects MCF-7 breast cancer and MDA-MB-435 melanoma cells against Taxol-induced apoptosis.
Samadi N, Gaetano C, Goping IS, Brindley DN.
Oncogene (2009) 28, 1028-1039.

9. Lysophosphatidate signaling stabilizes Nrf2 and increases the expression of genes involved in drug resistance and oxidative stress responses: implications for cancer treatment.
Venkatraman G, Benesch MG, Tang X, Dewald J, McMullen TP, Brindley DN.
FASEB J. (2015) 29, 772-785

10. Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance.
Bekele RT, Venkatraman G, Liu RZ, Tang X, Mi S, Benesch MG, Mackey JR, Godbout R, Curtis JM, McMullen TP, Brindley DN.
Sci Rep. (2016) 6, 21164

11. Inhibition of Autotaxin with GLPG1690 Increases the Efficacy of Radiotherapy and Chemotherapy in a Mouse Model of Breast Cancer.
Tang X, Wuest M, Benesch MGK, Dufour J, Zhao Y, Curtis JM, Monjardet A, Heckmann B, Murray D, Wuest F, Brindley DN.
Mol Cancer Ther. (2020) 19, 63-74

12. Human Cytomegalovirus Seropositivity and Viral DNA in Breast Tumors Are Associated with Poor Patient Prognosis.
Yang Z, Tang X, Hasing ME, Pang X, Ghosh S, McMullen TPW, Brindley DN, Hemmings DG.
Cancers (Basel) (2022) 14

13. Latent Cytomegalovirus Infection in Female Mice Increases Breast Cancer Metastasis.
Yang Z, Tang X, Meng G, Benesch MGK, Mackova M, Belon AP, Serrano-Lomelin J, Goping IS, Brindley DN, Hemmings DG.
Cancers (Basel) (2019) 11

Lab Members

Postdoctoral Fellow
Zelei Yang

Research Associate
Xiaoyun Tang


Selected Publications



Office: 357a HMRC

Lab: 357 HMRC

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