Abstract P3-07-14: Targeting ERR-α regulated lactate metabolism eliminates drug-resistant breast cancer cells
Quayle, L; Park, S; McDonnell, DP; Ottewell, PD; Holen, I
Published in: Cancer Research
Novel therapeutic strategies to eliminate chemo-resistant tumour cells responsible for the development of secondary lesions are essential in order to prevent breast cancer relapse. We have developed an in vitro model system enabling isolation of a putative metastasis-initiating breast cancer cell sub-population with a mitotically quiescent, drug-resistant phenotype. We hypothesise that this population is able to utilise oestrogen-related receptor-alpha (ERR-α)-regulated oxidative lactate metabolism and that inhibition of this critical survival pathway will result in elimination of tumour cells that have survived anti-cancer therapies.Flow cytofluormetric monitoring of Vybrant® DiD retention identified a mitotically quiescent sub-population (~0.05%) in MDA-MB-231 human breast cancer cells grown under high glucose (11mM) conditions. DiD-retaining cells accumulated in the G2/M phase of the cell cycle and were shown to be non-senescent following cytochemical analysis of β-galactosidase activity. Cytotoxicity assays with doxorubicin (0.40μM for 72 hours) demonstrated increased survival in the quiescent fraction (40.76%) compared with the rapidly dividing bulk cell population (1.63%, P ≤ 0.0001). Isolated drug-resistant cells contained a sub-fraction (~1%) that was able to form new clonal populations following cessation of treatment. Mitotically quiescent cells were cultured under high glucose (11mM) or glucose-depleted conditions with high lactate (22mM) in the presence of ERR-α inhibitors Cpd29 (10μM) or XCT790 (10μM). Colony formation was completely eliminated in Cpd29- and XCT790-treated samples compared to untreated controls. Drug-resistant sub-clones were isolated from the quiescent population following 72 hours treatment with doxorubicin (0.40μM) and were cultured under glucose-depleted conditions with high lactate (22mM) in the presence of ERR-α inhibitors Cpd29 (10μM) or XCT790 (10μM). In both instances, colony formation was completely prevented.We provide the first evidence that blocking cellular energy production through inhibition of ERR-α regulated oxidative lactate metabolism can eradicate a chemo-resistant, quiescent breast cancer cell population. Our data suggest that ERR-α inhibitors may be used in combination with chemotherapy to eliminate minimal residual disease and reduce breast cancer recurrence.Citation Format: Quayle L, Park S, McDonnell DP, Ottewell PD, Holen I. Targeting ERR-α regulated lactate metabolism eliminates drug-resistant breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-07-14.
