The secreted protein TINAGL1 inhibits TNBC progression and metastasis.

  • Major finding: The secreted protein TINAGL1 inhibits TNBC progression and metastasis.

  • Mechanism: TINAGL1 binds to EGFR and ITGB1 and respectively blocks the formation of EGFR:EGFR and ITGB1:FN complexes.

  • Impact: TINAGL1 is a potential prognostic biomarker and therapeutic agent for patients with TNBC.

Few therapeutic options are available for patients with triple-negative breast cancer (TNBC) due to the lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (encoded by ERBB2), all of which are currently clinically targetable. Further, TNBC, which is highly aggressive and metastatic, frequently exhibits both innate and adaptive drug resistance. Having previously shown that ablation of the secreted extracellular matrix (ECM) protein tubulointerstitial nephritis antigen-like 1 (TINAGL1) in breast cancer cells increased metastatic lung colonization, Shen and colleagues sought to further elucidate the mechanism underlying the role of TINAGL1 in breast cancer tumorigenesis. High TINAGL1 expression was found to be correlated with good prognosis in patients with TNBC, and weakly metastatic breast cancer cell lines exhibited higher TINAGL1 expression than highly metastatic cell lines. Further, constitutive and inducible overexpression of TINAGL1 or treatment with recombinant Tinagl1 (r-Tinagl1) reduced the growth and lung colonization of the LM2 cell line, a highly metastatic variant of MDA-MB-231. Immunoprecipitation–mass spectrometry profiling identified proteins involved in PI3K/AKT signaling, focal adhesion, and ECM-receptor interactions as potential TINAGL1 binding partners; coimmunoprecipitation confirmed the interactions of TINAGL1 with EGFR and integrin β1 subunit (ITGB1) and further showed that TINAGL1 interacts with integrins α5β1 and αvβ1, the two major receptors for fibronectin. Consistent with these findings, expression of TINAGL1 or treatment with r-Tinagl1 repressed EGFR and integrin/FAK signaling in LM2 cells. Mechanistically, TINAGL1 binds to EGFR to prevent ligand-induced EGFR dimerization and binds to ITGB1 to prevent the interaction between integrins α5β1 and αvβ1 with fibronectin. Pharmacologic inhibition of FAK/integrin signaling and/or EGFR revealed that suppression of both pathways was necessary to recapitulate the level of r-Tinagl1–mediated suppression of tumor growth and metastasis. These results characterize the role of TINAGL1 in TNBC tumorigenesis and metastasis and suggest potential therapeutic approaches.

Shen M, Jiang Y-Z, Wei Y, Ell B, Sheng X, Esposito M, et al. Tinagl1 suppresses triple-negative breast cancer progression and metastasis by simultaneously inhibiting integrin/FAK and EGFR signaling. Cancer Cell 2019;35:64–80.e7.

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