Abstract 2865: Dual action glycotherapy for triple negative breast cancer

Abstract

Abstract Triple negative breast cancer (TNBC; ER-/PR-/HER2-) accounts for 15% of all breast cancer with a disproportionate share of mortality. The patients are younger and pre-menopausal. The cancers are poorly differentiated, and most fall into the basal subgroup of breast cancers. The long-term survival is extremely low because of lack of specific treatment guidelines. Thus, the patients are managed with standard treatment. This causes a high rate of local and systemic relapse, and make patients resistant to existing targeted therapies (endocrine/biologics/adjuvant/neo-adjuvant). Anthracycline/taxane combination therapy and PARP inhibitor are currently being explored but not known what would be the outcome or if the patients would achieve a pathological complete response (pCR). Protein glycosylation has been claimed as an important feature helping cancer cells escaping immune surveillance, facilitate tumor invasion, and increased malignancy with increased tumor burden and poor prognosis as well as enhanced angiogenesis. Based on the glycomics profile of human breast cancer cells and tumor specimen, we have hypothesized that targeting asparagine-linked (N-linked) protein glycosylation would evolve a new generation therapeutic preventing breast tumor progression and eliminating the disease. Consequently, when treated with a homolog of protein N-glycosylation inhibitor tunicamycin the progression of a double negative breast cancer was inhibited significantly (J. Biol. Chem. 286, 29127-29138, 2011). We have now tested a triple negative breast tumor xenograft in athymic nude mice Balb/c (nu/nu) and the result is reduction of tumor progression (∼65% in one week) at tunicamycin concentration of 0.25 mg/Kg given orally twice a week. Human triple negative breast cancer cells (MDA-MB-231/MDA-MB-468) are equally susceptible to tunicamycin action. The cells are arrested in G1 and exhibit ER stress followed by induction of apoptosis mediated by unfolded protein response (upr) signaling. Western blotting and qRT-PCR support increased expression of the ER stress master regulator GRP78. But, the immunofluorescence microscopy could not detect GRP78 on the surface of control or tunicamycin treated cells. The result is identical in cells cultured in the absence of serum. GRP78 fluorescence however, is detectable in cells either fixed with ice-cold methanol or permeabilized with digitonin. We, therefore, conclude that GRP78 is not expressed on the outer-leaflet of the cell surface of the triple negative human breast cancer cells MDA-MB-231. But, its intracellular expression is anti-tumorigenic. Supported in part by grants from NSF-EPSCoR RII Track 1 Grant # EPS-1002410 (DKB) and NIH/NIMHD 2G12MD007583 (KB) Citation Format: Dipak K. Banerjee, Aditi Banerjee, Zhenbo Zhang, Jesus E. Serrano, Eva C. Romero, Neysharie Sanchez, Krishna Baksi. Dual action glycotherapy for triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2865.