Introduction: Why lncRNAs and MAPK Matter in Breast Cancer
Breast cancer is driven by a network of signaling pathways that control cell growth, survival, and metastasis. Among these, the mitogen-activated protein kinase (MAPK) cascades—comprising ERK, JNK, and p38—translate extracellular cues into precise cellular responses. In recent years, long non-coding RNAs (lncRNAs) have emerged as powerful regulators of MAPK signaling, acting as molecular sponges, guides, decoys, or scaffolds. Understanding how lncRNAs shape MAPK activity provides fresh angles for prognosis and targeted therapy in breast cancer across subtypes, including HR-positive, HER2-positive, and triple-negative breast cancers (TNBC).
MAPK Signaling in Breast Cancer: A Quick refresher
MAPK signaling proceeds through a three-tier module: MAP3K -> MAP2K -> MAPK. In breast cancer, ERK1/2 drives proliferation and survival, JNK influences stress responses and apoptosis, and p38 regulates inflammation, differentiation, and metastasis. Dysregulation—whether through mutations, upstream receptor signals, or feedback circuit alterations—can fuel tumor growth and resistance to therapy. The complexity of MAPK signaling is amplified by isoform-specific roles and cross-talk with other pathways such as PI3K/AKT, making lncRNAs attractive modulators of this network.
Key lncRNA Players Linking to ERK/MAPK in Breast Cancer
LINC00472 and LIMT: Tumor Suppressors That Tame MEK/ERK
In TNBC and basal-like cancers, LINC00472 dampens MEK/ERK signaling by downregulating MCM6, thereby inhibiting cell proliferation and metastasis. LIMT, another tumor suppressor, is repressed in ERK-active, basal-like tumors. By restraining EGFR-driven RAS-ERK signaling, LIMT curbs migration and invasion, highlighting how lncRNAs can buffer MAPK output to restrain cancer progression.
Oncogenic lncRNAs Enhancing ERK and Downstream Effectors
Several lncRNAs promote ERK-driven malignancy. For example, LINC00473 acts as a ceRNA for miR-198, lifting repression of MAPK1 (ERK2) and fueling tumorigenic traits. SNHG6 sponges miR-26a-5p to elevate MAPK6 (ERK3), driving proliferation and invasion. MALAT1 stabilizes SHOC2, augmenting ERK signaling via the RAS-RAF axis and contributing to metastasis and chemoresistance. These interactions demonstrate how lncRNAs sharpen ERK pathway signaling to favor tumor growth.
p38 Axis and lncRNA Regulation
p38 MAPK activity, particularly p38α, is essential for responses to stress and inflammation. LncRNAs such as ST8SIA6-AS1 can heighten p38 signaling in ER-/PR- breast cancers, promoting proliferation and invasion, while other lncRNAs like FOXCUT modulate p38 through ceRNA networks, illustrating context-dependent roles of lncRNA-p38 crosstalk in tumor biology.
lncRNA-JNK Communication: Resistance and Apoptosis
JNK signaling, a stress-responsive MAPK branch, can induce apoptosis or promote survival based on context. LncRNAs such as MIR100HG, CBR3-AS1, and HOTAIR influence JNK activity or its downstream targets, linking lncRNA profiles to therapy response. The MIR100HG axis in TNBC shows how lncRNA-driven JNK/MAPK remodeling can drive invasion and chemoresistance, emphasizing the need to profile lncRNAs when evaluating JNK-targeted therapies.
Clinical Implications: Therapeutic Targeting and Biomarkers
Therapeutically, disrupting lncRNA-MAPK interactions offers two promising angles: (a) directly targeting oncogenic lncRNAs or their interactions with MAPK components, and (b) combining lncRNA-targeted approaches with MAPK inhibitors (e.g., MEK or ERK inhibitors) to overcome resistance. Conversely, restoring tumor-suppressive lncRNA functions such as LINC00472 and LIMT could suppress MEK/ERK signaling and metastasis. The heterogeneity of breast cancer subtypes means that careful patient stratification—by ER/PR/HER2 status and MAPK activity—will be essential for leveraging lncRNA-based therapies effectively.
Future Directions: From Mechanisms to Medicine
Future research should prioritize: 1) validating lncRNA-MAPK interactions in patient-derived organoids and xenografts to capture tumor heterogeneity; 2) mapping ceRNA networks and identifying robust lncRNA biomarkers that predict MAPK dependence; 3) developing antisense oligonucleotides or small molecules that disrupt pathogenic lncRNA-MAPK interactions; and 4) designing combination regimens that pair lncRNA-targeting agents with existing MAPK inhibitors to prevent or overcome resistance. Integrating lncRNA biology into MAPK-targeted therapy holds promise for more precise, subtype-tailored treatments in breast cancer.
Conclusion: A New Layer in Breast Cancer Therapy
lncRNAs intricately regulate ERK, JNK, and p38 MAPK signaling to shape breast cancer progression, metastasis, and drug resistance. By decoding these networks, researchers can identify novel biomarkers and design combination therapies that disrupt cancer-favoring MAPK signaling while preserving normal cellular functions. The era of lncRNA-informed MAPK targeting is poised to enrich precision medicine for breast cancer patients.
