Introduction: The MAPK Landscape in Breast Cancer
MAPK signaling is a cornerstone of cellular decision-making, translating external cues into outcomes such as proliferation, differentiation, migration, and survival. In breast cancer, three major MAPK branches—ERK, JNK, and p38—coordinate responses to growth factors, cytokines, and stress signals. While mutations in upstream components frequently hijack this network, noncoding RNAs, especially long noncoding RNAs (lncRNAs), have emerged as potent modulators that fine-tune MAPK activity and shape tumor behavior. This article surveys how lncRNAs interface with MAPK signaling to influence breast cancer pathogenesis and therapy response.
The p38 MAPK Axis and lncRNA Regulation
The p38 MAPK pathway, activated by oxidative stress and inflammatory cues, controls inflammation, apoptosis, and differentiation. In breast cancer, p38 isoforms (p38α, β, γ, δ) exhibit context-dependent roles in tumor progression and metastasis. lncRNAs contribute to p38 regulation through diverse mechanisms. For instance, LINC00511 is upregulated in some breast cancers and correlates with poor prognosis by modulating p38 activity via a network that impacts MMP-13 and metastasis. Other lncRNAs, such as ST8SIA6-AS1, can enhance p38 signaling in triple-negative breast cancer (TNBC), illustrating how subtype context shapes lncRNA function. Conversely, several lncRNAs indirectly temper p38 signaling, underscoring a nuanced balance that governs tumor cell fate and treatment response.
ERK/MAPK Signaling: lncRNAs as Upstream Buffers and Downstream Effectors
The ERK branch, activated by RTKs and GPCRs, drives cell cycle progression and growth. lncRNAs act both upstream, by modulating receptor or adaptor signaling, and downstream, by influencing ERK targets. Examples include LINC00472, which suppresses ERK signaling by downregulating MCM6, thereby inhibiting TNBC progression. LIMT (LINC01089) serves as a metastasis-suppressor in basal-like and HER2-driven breast cancers by restraining EGFR-to-ERK flux. Other lncRNAs, such as LINC00473 and MALAT1, amplify ERK signaling via ceRNA networks that prevent microRNA-mediated repression of MAPK components like MAPK1 (ERK2) or SHOC2, promoting proliferation and metastasis or contributing to chemoresistance. In HER2-positive contexts, AC009283.1 and AC009283.1-associated networks link MAPK kinase cascades to VEGF production and anoikis resistance, highlighting how lncRNAs can rewire ERK-centered signaling to favor tumor survival. The emerging picture is that lncRNAs cassette-regulate ERK activity, shaping tumor growth, EMT, and drug response across breast cancer subtypes.
JNK Signaling and lncRNA-Mediated Modulation
JNKs respond to cellular stress and regulate apoptosis, differentiation, and invasion. In breast cancer, lncRNAs interface with JNK in both promoting and restraining tumor progression, depending on context. MIR100HG, for example, modulates a miRNA axis that influences JNK/MAPK components in TNBC, thereby controlling migration and invasion. The CBR3-AS1/miR-25-3p/JNK1/MEK4 axis demonstrates how lncRNAs can preserve JNK activity under chemotherapeutic stress, contributing to resistance. HOTAIR and JUNI further illustrate how lncRNAs can sustain JNK signaling and stress-adaptive responses, promoting survival and metastasis. Meanwhile, LASTR functions downstream of JNK to affect splicing of essential survival genes, offering a distinct therapeutic angle by targeting RNA processing rather than upstream signalingNodes. Collectively, these studies reveal a breadth of lncRNA strategies to tune JNK activity in breast cancer, influencing responses to therapy and disease progression.
<h2Unified view: lncRNA–MAPK networks driving breast cancer heterogeneity
Across p38, ERK, and JNK pathways, lncRNAs act as ceRNAs, scaffolds, and modulators of kinase activity, sculpting subtype-specific phenotypes. In TNBC and HER2-enriched tumors, lncRNAs such as LINC00472, LIMT, MIR100HG, and ST8SIA6-AS1 converge on the MEK/ERK axis or p38 signaling to promote or restrain proliferation, invasion, and resistance to therapy. In ER-positive disease, lncRNAs like LINC01089/LIMT and LINC00472 intersect with ERK signaling and cell cycle control, influencing endocrine therapy sensitivity. The ceRNA networks involving miRNAs (for example, miR-198, miR-24-3p, and miR-26a-5p) further connect lncRNA activity to MAPK outputs, creating robust regulatory circuits that can buffer against targeted inhibitors or foster adaptive resistance. Notably, several lncRNAs also affect upstream receptors (EGFR/IGF-1R) and downstream scaffolds (SHOC2, DUSP phosphatases), underscoring the layered control exerted by noncoding transcripts over MAPK signaling in breast cancer.
<h2Therapeutic implications and future directions
Harnessing lncRNA biology to modulate MAPK signaling offers a promising path to overcome resistance to MAPK inhibitors. Strategies include: targeting oncogenic lncRNAs with antisense oligonucleotides or siRNAs to dampen ERK or JNK activity; disrupting lncRNA–miRNA interactions that stabilize pro-tumor MAPK outputs; and combining lncRNA-targeted therapies with MEK/ERK or JNK inhibitors to prevent compensatory signaling. Patient-derived organoids and single-cell analyses will be essential to map subtype-specific lncRNA–MAPK networks and predict response to such therapies. As research advances, lncRNA-based biomarkers may guide the selection of MAPK inhibitors, enabling precision medicine for breast cancer patients with ER-positive, HER2-enriched, or TNBC subtypes.
Conclusion
lncRNAs modulate all major MAPK branches—p38, ERK, and JNK—driving breast cancer pathogenesis, metastasis, and treatment resistance. The nuanced, subtype-dependent effects of these noncoding RNAs emphasize the need for integrative studies that combine genomics, proteomics, and functional assays. By decoding lncRNA–MAPK networks, clinicians may one day tailor therapies that simultaneously target canonical signaling nodes and the RNA-based regulators that shape them, improving outcomes for diverse breast cancer patients.
