The invasive and metastatic phenotypes of breast cancer correlate with high recurrence rates and poor survival outcomes. Transforming growth factor-β (TGFβ) promotes tumor progression and metastasis in aggressive breast cancer. Here, we identified the kisspeptin KiSS1 as a downstream target of canonical TGFβ/Smad2 pathway in triple negative breast cancer cells. We also found KiSS1 expression to be required for TGFβ-induced cancer cell invasion. Indeed, knockdown expression of KiSS1 blocked TGFβ-mediated cancer cell invasion as well as metalloproteinase (MMP9) expression and activity. Interestingly, Kisspeptin-10 (KP-10), the smallest active form of kisspeptin also stimulates cancer cell invasive behavior through activation of MAPK/Erk pathway. We described a positive feedback loop between KiSS1 and p21 downstream of TGFβ, further contributing to TGFβ-induced cancer cell invasion. Lastly, we explored both the clinical utility of KiSS1 as a lymph node involvement predictive tool and its potential as a therapeutic target. We found KiSS1 high expression to correlate with lymph node positive status. Furthermore, blocking KiSS1 using a specific small peptide antagonist (p234) impaired TGFβ-mediated cell invasion and MMP9 induction. Together, our results define an essential role of KiSS1 in regulating TGFβ pro-invasive effects and define KiSS1 as a therapeutic new target for triple negative breast cancer.

乳腺癌的浸润性和转移性表型与高复发率和不良的生存结果相关。转化生长因子-β（TGFβ）促进侵袭性乳腺癌中的肿瘤进展和转移。在这里，我们确定了kisepteptin KiSS1是三阴性乳腺癌细胞中典型TGFβ/ Smad2途径的下游靶标。我们还发现KiSS1表达是TGFβ诱导的癌细胞侵袭所必需的。实际上，KiSS1的敲低表达阻止了TGFβ介导的癌细胞侵袭以及金属蛋白酶（MMP9）的表达和活性。有趣的是，吻肽素的最小活性形式Kisspeptin-10（KP-10）也通过激活MAPK / Erk途径刺激癌细胞的侵袭行为。我们描述了TGFβ下游KiSS1和p21之间的正反馈回路，进一步促进了TGFβ诱导的癌细胞侵袭。最后，我们探讨了KiSS1作为淋巴结受累预测工具的临床效用及其作为治疗靶标的潜力。我们发现KiSS1高表达与淋巴结阳性状态相关。此外，使用特定的小肽拮抗剂（p234）阻断KiSS1会损害TGFβ介导的细胞侵袭和MMP9诱导。总之，我们的研究结果确定了KiSS1在调节TGFβ侵袭性作用中的重要作用，并将KiSS1定义为三阴性乳腺癌的治疗新靶标。使用特定的小肽拮抗剂（p234）阻断KiSS1会损害TGFβ介导的细胞侵袭和MMP9诱导。总之，我们的研究结果确定了KiSS1在调节TGFβ侵袭性作用中的重要作用，并将KiSS1定义为三阴性乳腺癌的治疗新靶标。使用特定的小肽拮抗剂（p234）阻断KiSS1会损害TGFβ介导的细胞侵袭和MMP9诱导。总之，我们的研究结果确定了KiSS1在调节TGFβ侵袭性作用中的重要作用，并将KiSS1定义为三阴性乳腺癌的治疗新靶标。