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Review
. 2024 Aug 13;12(1):82.
doi: 10.1186/s40364-024-00633-6.

Trop2-targeted therapy in breast cancer

Yixuan Hu #  1 , Yinxing Zhu #  1   2 , Dan Qi  3 , Cuiju Tang  4 , Wenwen Zhang  5
Affiliations
Review

Trop2-targeted therapy in breast cancer

Yixuan Hu et al. Biomark Res. .

Abstract

Human trophoblastic cell surface antigen 2 (Trop2) is a glycoprotein, a cellular marker of trophoblastic and stem cells, and a calcium signaling transducer involved in several signaling pathways, leading to the proliferation, invasion, and metastasis of tumors. It is expressed at a low level in normal epithelial cells, but at a high level in many tumors, making it an ideal target for cancer therapy. According to previous literature, Trop2 is broadly expressed in all breast cancer subtypes, especially in triple negative breast cancer (TNBC). Several clinical trials have demonstrated the effectiveness of Trop2-targeted therapy in breast cancer. Sacituzumab govitecan (SG) is a Trop2-targeted antibody-drug conjugate (ADC) that has been approved for the treatment of metastatic TNBC and hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer. This article reviews the structure and function of Trop2, several major Trop2-targeted ADCs, other appealing novel Trop2-targeted agents and relevant clinical trials to provide a landscape of how Trop2-targeted treatments will develop in the future.

Keywords: Antibody-drug conjugate; Breast cancer; SG; TNBC; Targeted therapy; Trop2.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Structural characteristics of Trop2. The extracellular domain of Trop2 includes a cysteine-rich domain, a cysteine-poor domain and a thyroglobulin type-1 domain. The cytoplasmic tail includes a PIP2 binding sequence and two phosphorylation sites (S303 and S322)
Fig. 2
Fig. 2
Trop2-mediated signaling pathways. (A) Protein kinase C (PKC) can phosphorylate serine residue (S303) of the cytoplasmic tail of Trop2. Diacylglycerol (DAG) and inositol triphosphate (IP3) are created by the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2). IP3 can bind to specific endoplasmic reticulum receptors, release Ca2 + deposited there, increase intracellular calcium concentrations, and thus activate MAPK signaling pathways and promote cell proliferation. Ca2 + inhibits p16 expression through the AMP-activated protein kinase pathway. Increased phosphorylation of ERK1/2 enhances AP-1 and inhibits p27. The enhancement of AP-1 activity increased the expression of cyclin D1/E and CDKs. Trop2 also inhibits the expression of E-cadherin by stimulating the MAPK signaling pathway. In addition, DAG activates more PKC through a positive feedback mechanism, which increases Trop2 phosphorylation, thereby stimulating the Raf pathway and NF-κB. (B) Trop2 is hydrolyzed to ICD by TACE, γ-secretase, and PS-1/2. After the shed of Trop2-ECD, the co-localization of Trop2-ICD and β-catenin in the nucleus can induce the up-regulation of cyclin D1 and proto-oncogene c-myc downstream, thus promoting cell proliferation. (C) Trop2 overexpression leads to increased phosphorylation of p42 and p44 and increased Ki-67 levels. Trop2 inhibits apoptosis by increasing the expression of bcl-2 and decreasing the expression of bax. Trop2 also upregulates transcription factors (NF-κB and c-Jun) and downregulates transcription factors (CREB1, STAT1 and STAT3). Trop2 is involved in other signaling pathways, such as PI3K/Akt and JAK2/STAT3 signaling pathways. (D) Trop2 promotes the aggregation of RACK1 on the cell membrane, interacts with integrin β1 and talin, and promotes the localization of integrin α5β1/talin complex to the cell leading edge, away from focal adhesions. It also increases phosphorylation of kinases FAK, Src, and PAK4, and decreases Rac1-GTP levels, thus promoting invasion. (E) Trop2 can directly bind to the transmembrane proteins claudin1 and claudin7. Phosphorylation of Trop2 serine 322 leads to the relocalization of claudins, which leads to tumor cell migration. By interacting with NRG1 and IGF-1, Trop2 inhibits ErbB3 and IGF-1R signaling pathways, respectively, and thus exerts a tumor inhibitory effect
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