Breast cancer treatment has evolved drastically with the addition of immunotherapy and novel targeted drugs to the current treatment options. However, achieving long-term responses with minimal adverse events remains challenging. Cancer testis antigens (CTAs) offer novel opportunities for drug development thanks to their tumor specificity, immunogenicity, pro-tumorigenic functions, and negative prognostic connotations. We previously reported that lactate dehydrogenase C (LDHC) plays a key role in regulating genomic stability and that targeting LDHC significantly improved treatment response to DNA damage response drugs in breast cancer. Here, we explored the molecular mechanisms associated withLDHCsilencing in two basal-like breast cancer cell lines, MDA-MB-468 and BT-549, and a Her2-enriched breast cancer cell line, HCC-1954. Transcriptomic analyses identified the cell line-dependent differential activation of the pro-survival STAT3 pathway following LDHC depletion. WhileLDHCsilencing significantly compromised cell survival in basal-like breast cancer cells in conjunction with a downregulation of STAT3 signaling, the opposite effect was observed in Her2-enriched breast cancer cells, which demonstrated the enhanced activation of the pro-survival STAT3 signaling pathway. The inhibition of STAT3 not only reversed the unfavorable effect ofLDHCsilencing in the Her2-enriched cancer cells but also demonstrated significant anti-cancer activity when used as a single agent. Our findings suggest that the LDHC-STAT3 signaling axis plays a role in regulating breast tumor cell survival in a subtype-dependent manner. Thus, LDHC-targeted therapy could be a viable therapeutic approach for a subset of breast cancer patients, particularly patients with basal-like breast cancer, whereas patients carrying Her2-enriched tumors may likely benefit more from monotherapy with STAT3 inhibitors.
随着免疫疗法和新型靶向药物加入现有治疗方案，乳腺癌治疗已发生革命性进展。然而，如何在实现长期疗效的同时最大限度减少不良事件仍具挑战。癌睾丸抗原因其肿瘤特异性、免疫原性、促肿瘤发生功能及不良预后关联，为药物研发提供了新机遇。我们前期研究发现乳酸脱氢酶C在调控基因组稳定性中起关键作用，靶向LDHC能显著提升乳腺癌对DNA损伤应答药物的治疗反应。本研究通过两种基底样乳腺癌细胞系（MDA-MB-468与BT-549）及一种Her2富集型乳腺癌细胞系（HCC-1954），深入探索LDHC沉默的分子机制。转录组分析发现LDHC耗竭后，促生存STAT3通路呈现细胞系依赖性的差异化激活：在基底样乳腺癌细胞中，LDHC沉默通过下调STAT3信号显著削弱细胞存活能力；而在Her2富集型细胞中却观察到相反效应——促生存STAT3信号通路激活增强。STAT3抑制剂不仅能逆转LDHC沉默对Her2富集型癌细胞的不利影响，单药使用时也展现出显著抗癌活性。我们的研究提示LDHC-STAT3信号轴以亚型依赖方式调控乳腺肿瘤细胞存活。因此，靶向LDHC治疗可能成为特定乳腺癌亚群（尤其是基底样乳腺癌患者）的可行疗法，而Her2富集型肿瘤患者或许更能从STAT3抑制剂单药治疗中获益。
The LDHC-STAT3 Signaling Network Is a Key Regulator of Basal-like Breast Cancer Cell Survival
肿瘤(癌症)患者之家