Novel genes associated with lymph node metastasis in triple negative breast cancer

Abstract

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and no targeted treatments. TNBC patients are more likely to develop metastases and relapse than patients with other breast cancer subtypes. We aimed to identify TNBC-specific genes and genes associated with lymph node metastasis, one of the first signs of metastatic spread. A total of 33 TNBCs were used; 17 of which had matched normal adjacent tissues available, and 15 with matched lymph node metastases. Gene expression microarray analysis was used to reveal genes that were differentially expressed between these groups. We identified and validated 66 genes that are significantly altered when comparing tumours to normal adjacent samples. Further, we identified 83 genes that are associated with lymph node metastasis and correlated these with miRNA-expression. Pathway analysis revealed their involvement in DNA repair, recombination and cell death, chromosomal instability and other known cancer-related pathways. Finally, four genes were identified that were specific for TNBC, of which one was associated with overall survival. This study has identified novel genes involved in LN metastases in TNBC and genes that are TNBC specific that may be used as treatment targets or prognostic indicators in the future.

Role of RAD51AP1 in homologous recombination DNA repair and carcinogenesis

“…RAD51AP1 transcript was also found to be elevated (4- to 16-fold) in 19/21 intrahepatic cholangiocarcinomas (ICCs) and suppression of RAD51AP1 by shRNA resulted in growth suppression of cholangiocarcinoma cells, suggestive of the potential involvement of RAD51AP1 in promoting ICC development and/or progression [19]. RAD51AP1 transcript was shown to be overexpressed in aggressive mantle cell lymphoma compared to indolent small lymphocytic lymphoma [17], in HPV-positive squamous cell carcinoma of the head and neck (3.6-fold) compared to normal oral epithelium [56], in ovarian cancer as a consequence of downregulated microRNA hsa-mir-140-3p [57, 58], and in basal and triple-negative breast cancers compared to normal mammary tissue [53, 59]. Consistent with a potential role for RAD51AP1 in metastatic disease [51, 52], high RAD51AP1 expression was found to correlate with reduced time of survival of breast and ovarian cancer patients [58, 59].…”

Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers

“…Such a situation is further challenged by the fact that the disease is heterogeneous [8–10]. Although reports have indicated the involvement of certain genes/signaling molecules related to tumorigenic/metastatic pathways [5, 11–13] [14] in this subset of BC, there remains an unmet need for an in-depth study to establish a pathway-specific targeted therapy in TNBC, especially in the context of metastatic setting [15]. …”

RIPK3 upregulation confers robust proliferation and collateral cystine-dependence on breast cancer recurrence

“…This observation is supported by two human dataset of gene expression comparison between primary breast cancer and matching lymph node metastasis 28, 29 . First, RIPK3 mRNA was significantly increased by 2.08-fold in metastatic tumors when compared with primary human tumors (Supplemental Table 1) 28 .…”

“…First, RIPK3 mRNA was significantly increased by 2.08-fold in metastatic tumors when compared with primary human tumors (Supplemental Table 1) 28 . Another human dataset (GSE61723) 29 that compared 16 pairs of primary breast cancer and matching lymph node metastasis, also showed an increase in RIPK3 mRNA expression in 11 out of 16 pairs with an overall significant upregulation (Figure 1F). Collectively, these data indicate the upregulation of RIPK3 expression occurs in recurrent tumors in both a mouse model and two human studies.…”