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AACR 2023: Investigating the Role of ADSL in the Growth of Endocrine Therapy–Resistant Breast Cancer

By: Emily Rhode
Posted: Friday, May 12, 2023

Endocrine therapy resistance presents a major challenge in the treatment of patients with estrogen receptor–positive breast cancer. Results of a new study that aimed to establish the role of adenylosuccinate lyase (ADSL) in the growth of endocrine therapy–resistant, estrogen receptor–positive breast cancer cells were presented during the American Association for Cancer Research (AACR) Annual Meeting 2023 (Abstract 391/17). According to Surojeet Sengupta, PhD, of the Hormel Institute, University of Minnesota, Austin, and colleagues, the deficiency of ADSL, an enzyme involved in de novo purine biosynthesis, seems to impair the mitochondrial function and energy production of these breast cancer cells and may be a key component of their growth.

The study authors used the estrogen receptor–positive, endocrine therapy–resistant LCC9 and T47D-4HT cell lines to investigate the silencing RNA-mediated reduction of ADSL. They found that in both two-dimensional cell culture and spheroid formation, cell replication was reduced after ADSL depletion not because of cell death but on account of a disruption to the cell cycles in the two cell lines. Of note, the cycles of the two cell lines were arrested at different phases. When ADSL expression was decreased, the LCC9 cell cycle stopped at G1/S boundary, whereas T47D-4HT cells were blocked at the S/G2-M boundary. Moreover, both cell lines showed reduced levels of cyclin D1 protein at the time their cycles were disrupted.

Cells with ADSL deficiency also exhibited low levels of adenosine triphosphate (ATP) along with attenuated mitochondrial membrane potential. The authors noted that by adding a low concentration of aminoimidazole carboxamide ribonucleotide, a product of the de novo purine synthesis pathway, to LCC9 cells with low ATP, there was a partial rescue of reduced cell proliferation, and the mitochondrial membrane potential was restored. This outcome was not observed with the addition of adenosine monophosphate, adenosine, or fumarate.

Disclosure: The study authors reported no conflicts of interest.

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