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Breast cancer treatment identified in TMEM189

Researchers have revealed the new therapeutic potential of TMEM189 in the treatment of breast cancer.

A new study, published in Biochemical and Biophysical Research Communications, found that the knockdown of transmembrane protein 189 (TMEM189) significantly decreased the spread of breast cancer cells. Similarly, over-expression of the protein facilitated the proliferative capacity of tumour cells. 

Researchers from Shandong First Medical University and Shandong Academy of Medical Sciences used RNA-sequencing to better understanding how transmembrane protein 189 regulated breast cancer progression.

“Finding a new therapeutic target to efficiently induce tumour cell death without influencing normal cells is a crucial challenge for cancer management, including breast cancer,” the authors wrote.

Breast cancer and TMEM189

Breast cancer is a leading cause of tumour-related death among women around the world, but its pathogenesis is still unclear.

Transmembrane protein 189 (TMEM189) is widely expressed in many types of tissues and cells. A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane.

TMEM189 plays a critical role in tumorigenesis, partly through mediating cell death and is considered as a promising druggable target for developing anti-tumour therapy. However, its regulatory function on breast cancer progression and the underlying mechanisms have not been fully understood.

“The treatment failure for breast cancer is largely attributed to the incomplete understanding of its pathogenesis and associated mechanisms,” the authors noted.

Inducing ferroptosis

Constructed xenograft mouse models were used to validate the effects of TMEM189 in promoting breast cancer.  

Researchers then used RNA-sequencing and demonstrated that TMEM189 deletion was closely associated with ferroptosis signalling pathway. Ferroptosis is a type of programmed cell death featured by an iron-dependent accumulation of lipid peroxidation.

“Accumulating studies have shown that approaches to promote ferroptotic cell death is of great potential for the treatment of breast cancer,” the authors reported.

The team observed that ferroptosis  was accompanied with elevated lipid reactive oxygen species (ROS) accumulation, cellular ROS production, malondialdehyde (MDA) and the intracellular iron releases. However, GSH levels in breast cancer cells were highly impeded upon TMEM189 inhibition.

The researchers also observed that TMEM189 knockdown-induced ferroptotic cell death was considerably abolished after autophagy inhibitor 3-MA co-treatment. In addition, they found that over-expression of TMEM189 facilitated the proliferative capacity of tumour cells. 

The authors concluded, “Both In vitro and In vivo experiments demonstrated that TMEM189 deletion exerted anti-tumour function in breast cancer mainly through inducing ferroptosis via the mediation of autophagy.”

The work sheds light on the mechanisms revealing breast cancer cell ferroptosis, providing avenues for developing improved therapeutic approaches for breast cancer suppression.

Written by Poppy Jayne Morgan, Front Line Genomics

Image Credit: Canva