Overview: lncRNAs and the MAPK Signaling Web in Breast Cancer
Breast cancer pathogenesis is shaped by intricate signaling networks, with MAPK pathways acting as central hubs that govern proliferation, survival, migration, and angiogenesis. Long non-coding RNAs (lncRNAs) have emerged as influential regulators of these cascades, operating as molecular sponges, scaffolds, and downstream effectors. This article synthesizes current evidence on how lncRNAs interface with the ERK, JNK, and p38 MAPK modules to shape breast cancer biology, including therapy resistance and metastatic potential.
ERK/MAPK Axis: lncRNAs Orchestrating Proliferation and Drug Response
The ERK branch of MAPK signaling drives cell cycle progression and survival. In breast cancer, lncRNAs influence ERK activity through diverse mechanisms, including ceRNA networks and protein scaffolding. Notable examples include LINC00473, which sponges miR-198 to sustain MAPK1/ERK signaling and promote aggressive cell behavior, while also modulating cell cycle regulators. LINC00472 and LIMT function as tumor suppressors by dampening MEK/ERK signaling in TNBC and basal-like subtypes, highlighting how lncRNA context shapes outcomes across breast cancer subtypes. Other lncRNAs such as MALAT1 can enhance ERK signaling via SHOC2, reinforcing oncogenic ERK activation and contributing to metastasis and chemoresistance. In ER+ disease, linc-RoR affects ERK signaling by regulating DUSP7, a phosphatase that controls ERK phosphorylation, linking estrogen signaling to MAPK dynamics. The therapeutic implication is clear: targeting lncRNA–ERK interactions or the ERK effector axis could sensitize tumors to MEK inhibitors and overcome resistance to endocrine therapies.
Key lncRNA-ERK Axes in Subtypes
- LINC00472: suppresses MCM6 and lowers MEK/ERK activity, inhibiting TNBC progression.
- LIMT (LINC01089): acts as an ERK-controlled suppressor in EGFR-driven contexts, limiting metastasis.
- SNHG6: antagonizes miR-26a-5p to upregulate MAPK6 (ERK3), promoting malignancy.
JNK Pathway: lncRNAs Shaping Stress-Responsive and Metastatic Traits
JNK signaling, a stress-activated MAPK pathway, can exert contrasting roles in breast cancer depending on context. lncRNAs like MIR100HG can modulate the JNK axis through miRNA networks, where suppression of miR-5590-3p enhances JNK pathway activity and promotes TNBC aggressiveness. Other lncRNAs influence chemoresistance by engaging JNK at multiple levels: CBR3-AS1 sponges miR-25-3p to relieve inhibition on JNK1/MEK4, supporting survival under Adriamycin treatment, while HOTAIR intersects with JNK and p53 pathways to facilitate tamoxifen resistance. JUNI stabilizes JNK signaling by antagonizing DUSP14, sustaining pro-survival signaling under stress. Conversely, LASTR operates downstream of JNK, perturbing splicing via SART3 to undermine tumor cell fitness in stressed conditions, indicating a potential strategy to disrupt cancer-specific splicing without broad MAPK suppression.
p38 Pathway: lncRNA Regulation and Breast Cancer Progression
p38 MAPK, especially the p38α isoform, modulates inflammation, differentiation, and apoptosis, with isoform-specific roles in breast cancer. lncRNAs modulate p38 signaling through ceRNA networks and transcriptional control. For example, LINC00511 is linked to p38α/β targeting and breast cancer proliferation; ST8SIA6-AS1 can enhance p38 signaling to promote TNBC invasiveness but may harbor context-dependent tumor-suppressive roles in other settings. ST8SIA6-AS1, PRNCR1, FOXCUT, and AC009283.1 exemplify how lncRNAs orchestrate p38 activity to foster proliferation, migration, and angiogenesis via downstream targets like MMPs and VEGF. ST8SIA6-AS1–p38 interactions illustrate how breast cancer can co-opt environmental stress pathways for progression and metastasis, particularly in aggressive subtypes.
Integrated ceRNA Networks: Toward Precision Therapy
Across ERK, JNK, and p38 axes, lncRNAs frequently act within ceRNA networks, modulating miRNAs that target MAPK components. PTENP1, AC009283.1, and PRNCR1 exemplify lncRNAs with dual effects on MAPK and PI3K/AKT pathways, converging on proliferation and migration. The dual regulation by PTENP1 on MAPK and AKT highlights how lncRNAs can co-regulate multiple signaling routes, shaping a tumor’s responsiveness to targeted inhibitors. In TNBC, MIR100HG, LINC00472, LIMT, and LINC00473 collectively influence ERK-driven programs that govern metastasis and chemoresistance, suggesting combination strategies that pair MAPK inhibitors with lncRNA-targeted therapies.
Therapeutic Implications and Future Directions
Targeting lncRNA–MAPK crosstalk offers a promising route to overcoming resistance to MAPK inhibitors and endocrine therapies in breast cancer. Potential strategies include antisense oligonucleotides or small molecules to silence oncogenic lncRNAs (e.g., MIR100HG, HOTAIR, SNHG6) or to restore tumor-suppressive lncRNAs (e.g., LINC00472, LIMT). Additionally, combining lncRNA-targeted approaches with MEK/ERK inhibitors, JNK modulators, or p38 inhibitors could synergize to curb tumor growth and metastasis while mitigating compensatory pathway activation. As understanding of subtype-specific lncRNA–MAPK networks grows, personalized regimens tailored to ER+, HER2+, or TNBC contexts may become feasible, improving outcomes for patients facing aggressive breast cancers.
