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Bhasin, Satyam

University of British Columbia

Breast cancer (BCa) is a significant cause of cancer-related deaths among females globally. Approximately 45% of BCa patients develop treatment resistance or suffer from a lack of targeted therapies. Previously, we have shown that Semaphorin 3C (SEMA3C) is an autocrine growth factor that drives the growth and treatment resistance of various cancers. This study aims to investigate the functional role of SEMA3C in breast cancer progression and treatment resistance. My analysis of clinical datasets revealed elevated levels of SEMA3C mRNA in breast tumors compared to normal adjacent tissue. SEMA3C expression was positively correlated with the expression of various oncogenes implicated in breast cancer. Both estrogen receptor (ER) positive (ER⁺/HER2ˉ) BCa and triple negative breast cancer (TNBC) cells exhibited higher levels of SEMA3C protein compared to a non-cancer mammary epithelial cell line (MCF10A). Stimulation with recombinant SEMA3C activated EGFR, MAPK and AKT signaling in both ER⁺ and TNBC cells. Conversely, SEMA3C silencing inhibited ER expression, EGFR, MAPK, and AKT signaling, while inducing apoptosis. Silencing of SEMA3C significantly suppressed the growth of ER⁺ BCa and TNBC cells, indicating a growth dependency on SEMA3C. Tamoxifen-resistant cells (TamC3, TamR3) remained reliant on SEMA3C for growth and survival, suggesting its persistence in treatment resistance. Additionally, SEMA3C suppression enhanced the efficacy of certain chemotherapies and targeted therapies in TNBC cells. Additionally, treatment with SEMA3C pathway inhibitors, B1SP (Fc fusion protein) and ALS, attenuated SEMA3C-induced signaling and growth in both ER⁺ and TNBC cells. This study highlights the functional role of SEMA3C in breast cancer signaling and growth, suggesting its potential as a therapeutic target. Targeting SEMA3C may offer benefits in improving treatment outcomes for breast cancer patients, particularly in cases of endocrine treatment resistance and TNBC.

Text

2024-03-27

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/87643

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/