Abstract 2599: KDM3A tyrosine phosphorylation by Ack1 promotes tamoxifen-resistance in breast cancer

Abstract

Hormone therapy with the selective estrogen-receptor modulator tamoxifen (TAM) provides palliative benefit for patients with breast cancer. However, estrogen receptor α (ER hereafter) positive breast tumors with high expression of HER2 receptor tyrosine kinase often develop significant resistance to tamoxifen therapy. Thus, precise understanding of activation of Estrogen (E2)-independent ER regulated gene transcription in tamoxifen-resistant breast tumors could open new therapeutic avenues to target drug-resistance and ameliorate poor prognosis. The non-receptor tyrosine kinase, Ack1 (also known as TNK2) has emerged as a major integrator of signaling from various receptor tyrosine kinases including HER2. Here we demonstrate that heregulin promoted ER activity at Estrogen Response Element (ERE) in the presence of tamoxifen, which was significantly downregulated upon Ack1 knockdown. We observed that Ack1 phosphorylated the ER co-activator, KDM3A, a H3K9 demethylase, at evolutionary conserved tyrosine 1114 in heregulin dependent manner in the presence of tamoxifen. KDM3A demethylates H3 mono- and dimethyl-K9 in vitro and in vivo. Heregulin mediated Ack1 activation resulted in significant decrease in the level of monomethyl-H3K9, while, monomethyl-H3K27 levels remained unchanged. Further, inhibition of Ack1 by small molecule inhibitor AIM-100 or Dasatinib resulted in significant increase in the level of monomethyl-H3K9. Therefore by its ability to regulate the activity of ER co-activator such as KDM3A, activated Ack1 may modulate ER target gene expression in the absence of estrogen and confer TAM-resistance to cancer cells. Thus, Ack1 inhibitors hold the potential as novel therapeutics to treat a subset of tamoxifen resistant breast cancers. Citation Format: Kiran Mahajan, Sayantani Bandyopadhyay, Nupam Mahajan. KDM3A tyrosine phosphorylation by Ack1 promotes tamoxifen-resistance in breast cancer. [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 2599. doi:10.1158/1538-7445.AM2014-2599

Spatial and temporal clonal evolution of intrahepatic cholangiocarcinoma

“…(pAla776Val), a member of the Jumonji C-domain-containing histone demethylases involved in cisplatin-resistance in ovarian cancer and tamoxifen-resistance in breast cancer [22,23], was estimated to be clonal in regions R2, R3 and R8 but was subclonal in all other 8 regions ( Figure 1E). In fact, without multiregional WES, nearly 8% of subclonal mutations would be misinterpreted as clonal events.…”