Abstract 1983P
Background
Triple-negative breast cancer (TNBC) represents the most malignant subtype of breast cancer. Given the lack of ER and PR receptors and HER2 amplification/overexpression, targeted and hormone therapies are ineffective. The maximum tolerated dose is used as standard-of-care chemotherapy (STD); however, distant recurrences are frequent, remaining the first cause of death. Recently, metronomic chemotherapy (mCHT) – i.e., continuous chemotherapy using low toxic doses, without drug-free breaks – has been explored in many clinical trials showing a strong stabilization of cancer growth and improved cancer patients’ quality of life.
Methods
We investigated the impact of 5-FU+VNR given mCHT vs. STD on proliferation, migration, and colony formation of both endothelial and TNBC cells. MTT, colony formation, wound healing, and transwell assays were performed to investigate proliferative and migration capacity. Molecular mechanisms triggered upon STD or mCHT treatments were analyzed by Western blot.
Results
mCHT 5-FU+VNR is more effective than STD in reducing HUVECs viability, being the IC50 for HUVECs ∼10 times lower under the former. mCHT 5-FU+VNR is cytotoxic for both HUVECs and MDA-MB-231 cells given that no colonies re-grow 10 d after the end of treatment. Instead, under STD protocol colonies, re-growth was comparable to untreated control. Both STD and mCHT schedules significantly affected HUVECs’ migration ability via inhibiting MMP-2, whereas MDA-MB-231 cells migration was dramatically reduced only by mCHT. STD and mCHT affected VEGF/VEGFR/FAK signaling in either cell line; however, 5-FU+VNR can induce different cell death program, depending on the schedule, mCHT promoted HUVECs’ apoptosis, whereas it switched the modality of cell death from apoptosis, induced by STD, to autophagy in MDA-MB-231 cells.
Conclusions
mCHT 5-FU+VNR is more effective than STD in controlling cell proliferation and migration of HUVEC and TNBC cells. Moreover, the complete suppression of colonies after mCHT suggests that, conversely of STD, it may affect the metastatic capability of TNBC tumors, supporting experimental data from clinical trials.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
University of Milano-Bicocca.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.