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Simple Summary: Breast cancer remains the deadliest cancer among women worldwide. A major challenge in breast cancer care lies in the identification of drug targets that enable the specific killing of tumor cells without affecting normal cells. Previously, we showed that lactate dehydrogenase C (LDHC) plays an important role in regulating tumor genomic integrity and that targeting LDHC greatly reduces breast tumor cell survival and improves the efficacy of common anti-cancer drugs. The aim of our study was to gain insight into the molecular pathways that are associated with LDHC in tumors. Using three breast cancer cell lines, we found that the effect of LDHC targeting on tumor cell survival was negatively impacted by the activation of the STAT3 pathway in some cell lines and could be restored by STAT3 inhibition. Thus, LDHC is a viable target for breast cancer treatment in a subtype-specific manner. 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 with LDHC silencing 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. While LDHC silencing 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 of LDHC silencing 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. [ABSTRACT FROM AUTHOR]