The LDHC-STAT3 signaling network is a key regulator of long-term breast cancer cell survival.
Breast cancer treatment has evolved drastically with the addition of immunotherapy and novel targeted drugs. 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 demonstrated that targeting LDHC significantly improved treatment response to DNA damage response-drugs in breast cancer. Here, we explored the molecular mechanisms associated with LDHC silencing. Transcriptomic analyses identified cell-line dependent differential activation of the pro-survival STAT3 pathway following LDHC depletion. LDHC silenced cells that display STAT3 activation did not demonstrate excess DNA damage or reduced cell survival, and this effect could be reversed by inhibiting STAT 3. Our findings suggest that the LDHC-STAT3 signaling axis is critical for breast tumor cell survival. Hence, targeting LDHC in combination with STAT3 inhibition, in addition to targeting LDHC alone, could provide a novel therapeutic approach with minimal adverse effects.