Abstract 56: Examining the role of nm23-H1 in the metastatic profile of triple negative breast cancer (TNBC)
Authors: McGlothen Tanisha Z. , Tobin Rachel , Alcaide Tiffanie , Taliaferro-Smith LaTonia , Liu Tongrui , O'Regan Ruth 
Published: May 2015

Background: Triple negative breast cancer makes up 10-20% of all mammary tumors. It is so named because it exhibits low or no expression of both the estrogen receptor (ER) and progesterone receptor (PR), and has low or no expression of the human epidermal growth factor (HER2) receptor. With no current molecular target identified, treatments options for TNBCs are limited to conventional chemotherapy, which has been shown to be only moderately effective. Further, diagnosis is correlated with a high rate of relapse, low survival rate five years past diagnosis, and overall poor prognosis.

Nm23-H1 is the most well characterized in a class of tumor suppressor genes that have received increased attention as a potential therapeutic target in breast cancers. First identified in 1988, nm23, has been shown have low levels of mRNA expression in highly metastatic tumor cells, compared to normal or non-neoplastic tissue. This expression level coincides with not only increased metastasis but poor clinical prognosis in several type cancers, including breast cancer. Further, nm23-H1 inhibits a class of Rho small GTPases including Rac1, Rho and cdc42. These proteins mediate cell-to-cell adhesion and cytoskeletal reorganization, which ultimately moderate the metastatic profile i.e. metastasis, cellular motility, and invasion.

Methods: Western blotting was used to examine the basal level of expression in a panel of mesenchymal and epithelial TNBC cell lines. Transient siRNA was used to silence nm23-H1 in MDAMB231 and HCC1806 cells to determine the effects on downstream Nm23-H1 targets Rac1, Rho and cdc42. The effects of nm23-H1 inhibition on the invasive potential of TNBC cells were assessed using Matrigel chamber assays. Wound healing assays were employed to assess the effects of nm23-H1 inhibition on the migratory potential of TNBC cells.

Results: Our studies indicate that nm23-H1 is expressed in all of the TNBC cell lines that we tested but to varying degrees with mesenchymal cells expressing the protein at a higher level compared to epithelial cells. Immunoblotting suggested that silencing of nm23-H1 resulted in an increase in p-Rac. Silencing also increased the invasive ability of TNBC cells compared to control cells.

Conclusion: These results demonstrate the vital role that nm23-H1 plays in the inhibition of cellular invasion in TNBCs. An increase in the expression of proteins associated with motility and invasion pathways validates the role of nm23-H1 in inhibiting the metastatic profile in TNBC. As a potential molecular marker for metastatic TNBC, nm23-H1 warrants further investigation.

Citation Format: Tanisha Z. McGlothen, Rachel Tobin, Tiffanie Alcaide, LaTonia Taliaferro-Smith, Tongrui Liu, Ruth O'Regan. Examining the role of nm23-H1 in the metastatic profile of triple negative breast cancer (TNBC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 56. doi:10.1158/1538-7445.AM2014-56