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

Biochem Biophys Res Commun. 2022 Jan 15:588:175-181. doi: 10.1016/j.bbrc.2021.12.056. Epub 2021 Dec 20.


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.

Keywords: Endothelial cell tube formation; HER2-Positive breast cancer; Trastuzumab resistance; αB-crystallin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Culture Media, Conditioned / pharmacology
  • Drug Resistance, Neoplasm* / drug effects
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Female
  • Humans
  • Neovascularization, Physiologic* / drug effects
  • Phosphorylation / drug effects
  • TOR Serine-Threonine Kinases / metabolism*
  • Trastuzumab / pharmacology
  • Trastuzumab / therapeutic use*
  • alpha-Crystallin B Chain / metabolism*


  • Culture Media, Conditioned
  • alpha-Crystallin B Chain
  • TOR Serine-Threonine Kinases
  • Trastuzumab