Abstract CCN5, a matricellular protein, represents promising treatment target in triple negative breast cancer (TNBC) as treatment or induced activation of CCN5 in TNBC cells promotes cell growth arrest at G0/G1 phase, reduces cell proliferation and delays tumor growth in xenograft model. Our studies found that p27Kip1 tumor suppressor protein is upregulated and relocalized to the nucleus from cytoplasm by CCN5 in these cells and that these two events (i.e., upregulation and relocalization) of p27Kip1 is required for CCN5-induced growth inhibition of TNBC cells. In the absence of CCN5, p27Kip1 remains mostly in the cytoplasm, a state of aggressive nature of cancer cells. Mechanistically, CCN5 inhibits Skp2 expression, which seems to stabilize p27Kip1 protein in these cells. On the other hand, CCN5 also recruits FOXO3a to mediate transcriptional regulation of p27Kip1. The recruitment of FOXO3a is achieved by the induction of its expression and activity through shifting from cytoplasm to the nucleus. Our data indicate that CCN5 blocks PI3K/AKT signaling to dephosphorylate at S318, S253 and Thr32 in FOXO3a for nuclear relocalization and activation of FOXO3a. Inhibition of α6β1 diminishes CCN5 action on p27Kip1 in TNBC cells. Collectively, CCN5 may have therapeutic potential for TNBC. Citation Format: Inamul Haque, Snigdha Banerjee, Archana De, Gargi Maity, Sandipto Sarkar, Douglas McGragor, Sushanta K. Banerjee. CCN5/wisp-2 induced growth arrest of aggressive triple negative breast cancer cells is promoted through accumulation and trafficking of p27kip1 . [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 1552. doi:10.1158/1538-7445.AM2014-1552