Alpha-crystallin B chains in trastuzumab-resistant breast cancer cells promote endothelial cell tube formation through activating mTOR

• Published in: Biochemical and biophysical research communications 2022-01, Vol.588, p.175-181
• Main Authors: Yang, Lili, Higashisaka, Kazuma, Shimoda, Masafumi, Haga, Yuya, Sekine, Naoki, Tsujino, Hirofumi, Nagano, Kazuya, Shimazu, Kenzo, Tsutsumi, Yasuo
• Format: Article
• Language: English
• Subjects: alpha-Crystallin B Chain - metabolism; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Line, Tumor; Culture Media, Conditioned - pharmacology; Drug Resistance, Neoplasm - drug effects; Endothelial cell tube formation; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Female; HER2-Positive breast cancer; Humans; Neovascularization, Physiologic - drug effects; Phosphorylation - drug effects; TOR Serine-Threonine Kinases - metabolism; Trastuzumab - pharmacology; Trastuzumab - therapeutic use; Trastuzumab resistance; αB-crystallin
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2021.12.056

The specific human epidermal growth factor receptor 2 (HER2)-targeting monoclonal antibody trastuzumab shows considerable clinical efficacy in patients with HER2-overexpressing breast cancer. However, about 20% of patients who receive trastuzumab in the adjuvant setting relapse, and approximately half of patients with metastatic HER2-positive breast cancer develop resistance to trastuzumab within 1 year. Although the mechanism of trastuzumab resistance has been explored broadly, whether and how angiogenesis participates in trastuzumab resistance is unclear. Here, we examined the association between angiogenesis and trastuzumab resistance by using a trastuzumab-resistant cell line (SKBR3-TR). Compared with that from the parental trastuzumab-sensitive SKBR3 cells, the culture supernatant from SKBR3-TR cells significantly increased the sprouting of endothelial cells. To identify intercellular features that contribute to the induction of endothelial tube formation, proteomics revealed that α-crystallin B chain (αB-crystallin) was upregulated in SKBR3-TR cells. Moreover, silencing of αB-crystallin significantly repressed SKBR3-TR-induced tube formation, and knockdown of αB-crystallin in SKBR3-TR cells suppressed the activation of mechanistic target of rapamycin (mTOR) in endothelial cells. In addition, treatment with rapamycin, an inhibitor of mTOR, reversed the SKBR3-TR-induced promotion of tube formation. In summary, αB-crystallin enhanced the ability of SKBR3-TR cells to activate mTOR in endothelial cells and thus promote angiogenesis. •Increased αB-crystallin level of SKBR3-TR cells promoted tube formation by HAECs.•Silencing αB-crystallin in SKBR3-TR cells suppresses p-mTOR in endothelial cells.•Rapamycin suppressed tube formation in HAECs induced by SKBR3-TR cells.