A single enzyme might hold the key to understanding why some of the most aggressive breast cancers resist treatment.
A New Clue in Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) stands as the most challenging breast cancer subtype to treat. Its name comes from the absence of three receptors that most therapies target, leaving clinicians with fewer options. This cancer disproportionately affects African American women, who face higher incidence rates and often worse clinical outcomes 3 .
Triple-negative breast cancer lacks estrogen receptors, progesterone receptors, and HER2 protein, making it unresponsive to hormonal therapies or drugs that target HER2.
For years, researchers have struggled to understand the drivers of this disparity. Is it rooted in biology, or is it the result of social and healthcare inequities? Recent groundbreaking genomic studies suggest the biological differences at the level of acquired mutations may be smaller than previously thought 1 6 . At the same time, scientists are looking beyond genetics to cancer metabolism, where a protein called Lactate Dehydrogenase A (LDHA) has emerged as a crucial player in making TNBC aggressive and hard to treat 2 7 .
To understand the excitement around LDHA, one must first understand how cancer cells fuel their growth.
In the 1920s, Otto Warburg observed a bizarre phenomenon. Unlike healthy cells that efficiently produce energy using oxygen, cancer cells voraciously consume glucose and convert it to lactate, even when oxygen is plentiful. This process, known as aerobic glycolysis or the Warburg effect, is a hallmark of cancer 4 7 .
Lactate Dehydrogenase A is the engine of this process. It performs the final, critical step in glycolysis: converting pyruvate into lactate 4 . This action allows the cancer cell to rapidly regenerate the molecules it needs to keep consuming glucose and growing uncontrollably. In essence, LDHA acts as a metabolic accelerator for tumors.
Research has revealed that LDHA's role extends far beyond mere energy production.
Perhaps most critically, LDHA is now recognized as a major contributor to tumor drug resistance 7 . By promoting the "stemness" of cancer cells—their ability to self-renew and resist therapy—and by shaping the tumor microenvironment to suppress immune attacks, LDHA helps cancers survive chemotherapy, radiotherapy, and immunotherapy 7 .
High LDHA expression correlates with poor patient outcomes across multiple cancer types, making it a valuable biomarker for prognosis and treatment planning.
A significant 2025 study published in BMC Women's Health brought LDHA into sharp focus in the context of breast cancer, providing critical evidence of its clinical relevance 2 .
They analyzed genetic data from The Cancer Genome Atlas (TCGA) to assess LDHA expression in breast cancer tissues compared to normal breast samples 2 .
Using statistical models, they examined the relationship between high LDHA levels and patient outcomes, including overall survival and recurrence-free survival. They also explored connections between LDHA and the tumor's immune microenvironment 2 .
The team then turned to real-world data from an institutional cohort of 529 breast cancer patients at Harbin Medical University Cancer Hospital. They tested whether baseline levels of serum LDH (the enzyme measured in blood tests, reflecting LDHA activity) could predict which patients would achieve a pathological complete response (pCR) after neoadjuvant chemotherapy. pCR, meaning no detectable cancer remains after pre-surgical treatment, is a powerful predictor of long-term survival 2 .
Finally, they used National Health and Nutrition Examination Survey (NHANES) data to examine the broad association between serum LDH levels and mortality risk in the general population 2 .
The findings from this comprehensive study were striking.
| Aspect Investigated | Finding | Clinical Implication |
|---|---|---|
| LDHA in Tumor Tissue | Upregulated in BC tissues vs. normal | Potential diagnostic marker |
| Patient Survival | High LDHA linked to worse OS, RFS, DMFS | Powerful prognostic indicator |
| Chemotherapy Response | Low serum LDH associated with higher pCR rates | Predictor of treatment efficacy |
| Population Health | High serum LDH linked to increased mortality | Validates its broad biological importance |
So, how does LDHA connect to the specific challenges faced by African American women with TNBC? The link, for now, is based on a compelling convergence of evidence rather than a single study.
A landmark 2025 genomic study in Nature Genetics that analyzed TNBC tumors from 462 African American women found that the somatic mutational landscape was largely similar to that of Asian and non-Hispanic white women 1 5 6 . The lead author, Dr. Song Yao, noted that their "data do not support major racial differences in TNBC biology at the level of somatic mutations" 1 . This points away from inherited genetic mutations being the primary driver of the disparity.
The same study identified that TNBC in African American women appears to develop through two main pathways: one related to genetic predisposition in younger patients, and another, found more often in older patients, that is related to aging and the effects of obesity 1 . Obesity is a known risk factor for TNBC and is more prevalent among African American women 3 .
This is where LDHA becomes a prime suspect. Obesity can create a state of chronic inflammation and metabolic dysregulation in the body 3 . In this environment, the metabolic reprogramming fueled by LDHA could be particularly advantageous for cancer cells. Furthermore, the 2025 LDHA study confirms that its expression correlates with worse outcomes and treatment resistance across breast cancer 2 . While more research is needed to directly link LDHA to TNBC disparities, its established role in aggression and therapy resistance makes it a critical piece of the puzzle.
| Factor | Hypothesized Role | Evidence |
|---|---|---|
| Biology (e.g., LDHA) | Drives tumor aggression and resistance to therapy 2 7 . | High LDHA expression is linked to poor survival and chemo resistance in BC 2 . |
| Social & Environmental | Influences risk factors and access to care 3 . | Obesity, stress, and lack of healthcare access are more common in AA women 3 . |
| Genomics | Determines inherited predisposition and somatic mutations. | Somatic mutational landscape of TNBC is similar across racial groups 1 6 . |
The growing understanding of LDHA's role has catalyzed the development of new therapeutic strategies. The field is moving beyond simple enzyme inhibition to more sophisticated disruption methods.
| Tool / Approach | Function | Research Goal |
|---|---|---|
| Active-Site Inhibitors | Binds to the enzyme's active site to block its function 8 . | Directly shut down lactate production. |
| Tetramerization Disruptors | Prevents four LDHA subunits from forming the active tetramer complex 8 . | Indirectly deactivate LDHA by breaking its structure. |
| miRNA Mimics (e.g., miR-34a) | Silences LDHA gene expression by targeting its mRNA 4 7 . | Reduce the production of the LDHA protein. |
| Transcriptional Repression | Targets upstream regulators like HIF-1α or c-Myc to reduce LDHA transcription 4 7 . | Switch off the "instructions" for making LDHA. |
One promising avenue is disrupting LDHA tetramerization. Since LDHA must form a four-part structure (a tetramer) to be active, researchers are using computer-aided drug design to find natural compounds that can break this structure apart. This approach could offer better selectivity and fewer side effects than traditional active-site inhibitors 8 .
The story of LDHA in triple-negative breast cancer is a powerful example of how cancer research is evolving. It shows a shift from a purely genetic perspective to a metabolic one, where the very way a cancer cell fuels itself becomes its weakness.
For African American women facing a disproportionate burden of TNBC, the investigation into proteins like LDHA is particularly urgent. While biology may not be the sole driver of disparities, understanding the metabolic mechanisms that make TNBC aggressive opens new doors for everyone. LDHA serves as both a beacon for future targeted therapies and a practical biomarker that could soon help oncologists identify which patients need more aggressive or novel treatment strategies upfront.
The road from discovery to treatment is long, but the path is clear. As research continues to untangle the complex web of biology, environment, and social factors, the goal remains the same: to turn the most aggressive cancers into manageable diseases and ensure that advances in care benefit all patients equally.