Currently, breast cancer is one of the most frequently diagnosed cancers and is the 5th leading cause of death from cancer. Globally, it is estimated that 2.3 million new cases of breast cancer are diagnosed each year. Despite an increase in breast cancer cases, survival rates have enhanced in recent years due to the profound research on the biological behavior of breast cancer. Numerous strategies like screening programs along with general preventative measures can be undertaken to reduce the incidence rate of breast cancer and to avail early treatment [1].
Current therapeutic approach for breast cancer
The first-line treatments for various stages of breast cancer consist of:
Radiotherapy
Chemotherapy
Surgery
Depending on the characteristics of the tumor, this is either utilized alone or in conjunction with endocrine and/or targeted therapy. Unfortunately, some cancers become resistant to radiotherapy and chemotherapy and become refractory. If treatment failure occurs, patient’s survival rates and quality of life are dramatically impacted. The absence of treatments that can overcome this resistance or suppress the survival signals coming from the tumor microenvironment is a significant hindrance in treating this situation [2].
What is autotaxin?
Autotaxin (ATX) is a secreted glycoprotein that produces lysophosphatidate (LPA), which is a lipid mitogen and motility factor. LPA signals through six G protein-coupled receptors to promote cell division, cell movement, survival, and angiogenesis. The level of expression of ATX in tumors determines the aggressiveness and invasiveness of the tumor.
Human melanoma A2058 cells were the first to exhibit ATX, and it has since been found in several additional tumor cell lines. In breast cancer as well as other types of cancer ATX expression determines:
Tumor growth
Invasion
Metastasis
Response to chemotherapy and radiotherapy.
At this time, it is unclear exactly how ATX alters cell signaling to promote angiogenesis, cancer cell motility, and metastasis[3].
How autotaxin is a therapeutic target in breast cancer?
Breast cancer cells express little ATX, however, many cancer cells produce ATX. ATX is produced by tumor-associated stroma in breast cancers. A major biological source of ATX is adipose tissue which surrounds breast cancers as well. Breast cancers generate inflammatory mediators that trigger ATX transcription in adipose tissue adjacent to the tumor. This drives a vicious cycle of inflammation since higher LPA signaling triggers the future generation of inflammatory mediators and cyclooxygenase-2. Attenuating ATX activity breaks this cycle, which has implications for breast cancer adjuvant therapies. Independent of the type of breast cancer, targeting ATX activity and LPA signaling may improve the effectiveness of chemotherapy and radiotherapy while reducing radiation-induced fibrosis morbidity [3].
There is currently enough evidence to prove that ATX promotes tumor growth, metastasis, and a reduction in the effectiveness of chemotherapy and radiotherapy. However, there is not a definite strategy for specifically targeting ATX for cancer treatment. According to prior research studies, inhibiting ATX activity may improve the antitumor effect of chemotherapy and radiotherapy when used in combination. Because the majority of the ATX is not formed from breast cancer cells, this effect is probably independent of the kind of breast cancer [3].
A time of reckoning
The scientific evidence demonstrates that blocking ATX and subsequent LPA signaling in the tumor microenvironment may offer a potential adjuvant therapy to enhance the effectiveness of radiotherapy and chemotherapy in patients with breast cancer. The benefits of inhibiting the ATX activity in vivo by roughly 80% could diminish the activation of all LPA receptors. However, other physiological processes that depend on LPA-mediated signaling may be impacted by such widespread inhibition. For instance, blocking LPA4 and LPA5 receptors, which impede cancer cell proliferation and motility, might not be a good idea. The ability of cancer cells to evade the immune system, however, might be reduced hypothetically if LPA5 receptor activity is blocked [3].
ATX inhibition in breast cancer: future perspectives
The interaction between ATX inhibitors and the use of checkpoint inhibitors and other immune therapies has not been explored much, although it may be a useful field for cancer research. This is an exciting time when the development of new drugs that can reduce the activation of the ATX-LPA-inflammatory cycle may upshot in the development of effective adjuvant therapy for the treatment of breast cancer patients.
References
1. Łukasiewicz, S. et al. 'Breast Cancer—Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies—An Updated Review'. Cancers (Basel). (2021) 13(17), 4287. DOI: 10.3390/cancers13174287.
2. Tang, X. et al. 'Inhibition of Autotaxin with GLPG1690 Increases the Efficacy of Radiotherapy and Chemotherapy in a Mouse Model of Breast Cancer'. Molecular Cancer Therapeutics. (2020) 19(1), 63–74. DOI: 10.1158/1535-7163.MCT-19-0386.
3. Brindley, D.N. et al. 'Role of Adipose Tissue-Derived Autotaxin, Lysophosphatidate Signaling, and Inflammation in the Progression and Treatment of Breast Cancer'. Int J Mol Sci. (2020) 21(16), 5938. DOI: 10.3390/ijms21165938.
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