Targeting KK-LC-1 inhibits malignant biological behaviors of triple-negative breast cancer

Background: Cancer/testis antigens (CTAs) participate in the regulation of malignant biological behaviors in breast Cancer. However, the function and mechanism of KK-LC-1, a member of the CTA family, in breast Cancer are still unclear.

Methods: Bioinformatic tools, immunohistochemistry, and western blotting were utilized to detect the expression of KK-LC-1 in breast Cancer and to explore the prognostic effect of KK-LC-1 expression in breast Cancer patients. Cell function assays, animal assays, and next-generation Sequencing were utilized to explore the function and mechanism of KK-LC-1 in the malignant biological behaviors of triple-negative breast Cancer. Small molecular compounds targeting KK-LC-1 were also screened and drug susceptibility testing was performed.

Results: KK-LC-1 was significantly highly expressed in triple-negative breast Cancer tissues than in normal breast tissues. KK-LC-1 high expression was related to poor survival outcomes in patients with breast Cancer. In vitro studies suggested that KK-LC-1 silencing can inhibit triple-negative breast Cancer cell proliferation, invasion, migration, and scratch healing ability, increase cell Apoptosis ratio, and arrest the cell cycle in the G0-G1 phase. In vivo studies have suggested that KK-LC-1 silencing decreases tumor weight and volume in nude mice. Results showed that KK-CL-1 can regulate the malignant biological behaviors of triple-negative breast Cancer via the MAL2/MUC1-C/PI3K/Akt/mTOR pathway. The small-molecule compound Z839878730 had excellent KK-LC-1 targeting ability and Cancer cell killing ability. The EC₅₀ value was 9.7 μM for MDA-MB-231 cells and 13.67 µM for MDA-MB-468 cells. Besides, Z839878730 has little tumor-killing effect on human normal mammary epithelial cells MCF10A and can inhibit the malignant biological behaviors of triple-negative breast Cancer cells by MAL2/MUC1-C/PI3K/Akt/mTOR pathway.

Conclusions: Our findings suggest that KK-LC-1 may serve as a novel therapeutic target for triple-negative breast Cancer. Z839878730, which targets KK-LC-1, presents a new path for breast Cancer clinical treatment.

Breast cancer; KK-LC-1; MAL2; MUC1-C; Prognosis; Targeted drug; Tumor metastasis.