How Different Are the Molecular Mechanisms of Nodal and Distant Metastasis in Luminal A Breast Cancer?

Abstract

Lymph node status is one of the best prognostic factors in breast cancer, however, its association with distant metastasis is not straightforward. Here we compare molecular mechanisms of nodal and distant metastasis in molecular subtypes of breast cancer, with major focus on luminal A patients. We analyze a new cohort of 706 patients (MMCI_706) as well as an independent cohort of 836 primary tumors with full gene expression information (SUPERTAM_HGU133A). We evaluate the risk of distant metastasis, analyze targetable molecular mechanisms in Gene Set Enrichment Analysis and identify relevant inhibitors. Lymph node positivity is generally associated with NF-κB and Src pathways and is related to high risk (OR: 5.062 and 2.401 in MMCI_706 and SUPERTAM_HGU133A, respectively, p < 0.05) of distant metastasis in luminal A patients. However, a part (≤15%) of lymph node negative tumors at the diagnosis develop the distant metastasis which is related to cell proliferation control and thrombolysis. Distant metastasis of lymph node positive patients is mostly associated with immune response. These pro-metastatic mechanisms further vary in other molecular subtypes. Our data indicate that the management of breast cancer and prevention of distant metastasis requires stratified approach based on targeted strategies.

Desmocollin-1 is associated with pro-metastatic phenotype of luminal A breast cancer cells and is modulated by parthenolide

“…For luminal A subtype, well established and effective treatment includes hormone therapy that targets estrogen and progesterone receptors and is based on tamoxifen or aromatase inhibitors [ 8 , 9 ]. However, up to 16% of node-negative luminal A patients and up to a third of lymph node positive luminal A patients at the time of diagnosis develop distant metastasis [ 10 , 11 ]. Moreover, about 20% to 30% of patients with estrogen receptor-positive tumors become resistant to the endocrine treatment [ 12 ].…”

Global Interactome Mapping Reveals Pro-tumorigenic Interactions of NF-κB in Breast Cancer

“…As the NF-κB is best known as a key regulator of inflammation and immune response ( 83 , 84 , 85 ), we indeed detected rearrangement of protein complexes involved in NF-κB signaling, innate immune response, antigen presentation, and IL-1 pathways. However, other studies demonstrated NF-κB pathway to support cancer development and progression, including lymph node metastasis of luminal A breast tumors ( 16 , 17 ), as it contributes to number of other cellular processes and promotes cellular growth and proliferation ( 86 , 87 , 88 ). We demonstrated the effects of NF-κB activity on composition of protein complexes associated with regulation of cell cycle and Wnt pathway that represents an important therapeutic target in breast cancer ( 89 , 90 ).…”

“…Nevertheless, former studies linked aberrant activity of NF-κB with cancer, including enhanced expression of NF-κB factors in breast cancer cells as well as their participation in breast tumorigenesis ( 9 , 11 , 12 , 13 , 14 , 15 ). Our previous studies ( 16 , 17 ) identified association between increased transcript and protein NF-κB levels and lymph node metastasis of luminal A breast tumors. Inhibition of NF-κB thus hypothetically represents a potential anti-metastatic therapeutic strategy for this group of tumors.…”

Is Metastatic Staging Needed for All Patients with Synchronous Bilateral Breast Cancers?

“…While nodal status was predictive of systemic metastasis, patients with negative nodal status could still have systemic metastasis [ 31 ]. Conversely, not all patients with positive nodal status would have systemic metastasis; hence, the relationship between nodal status and systemic metastasis is not unequivocal [ 32 ]. It was reported that about one-third of breast cancer patients with a negative nodal status could still develop systemic metastasis, while one-third of breast cancer patients with a positive nodal status do not develop systemic metastasis at all [ 32 ].…”

“…Conversely, not all patients with positive nodal status would have systemic metastasis; hence, the relationship between nodal status and systemic metastasis is not unequivocal [ 32 ]. It was reported that about one-third of breast cancer patients with a negative nodal status could still develop systemic metastasis, while one-third of breast cancer patients with a positive nodal status do not develop systemic metastasis at all [ 32 ]. Despite this, nodal status remained the most predictive factor for systemic metastasis at staging in our study.…”