Abstract A120: Dissecting the role of AGR2 in breast cancer
Authors: Hrstka Roman , Brychtova Veronika , Nenutil Rudolf , Fabian Pavel , Vojtesek Borek 
Published: May 2015

Breast cancer is the most common women′s malignity, with growing incidence primarily in advanced countries. Hormone sensitive tumors, characterized by expression of estrogen and progesterone receptors, represent the largest group of breast carcinomas. The presence of estrogen receptors (ER) and progesterone receptors (PgR) indicates response to endocrine therapy and improved disease-free survival (1). The most frequent therapy for estrogen receptor positive breast cancer malignancies is functional blockage of estrogen receptors by tamoxifen. Although tamoxifen is treatment of choice and estrogen receptor targeting is responsible for improvements in cure rates of breast cancers, the therapy itself is limited by frequently developed drug resistance (2).

As the endocrine resistance is a significant problem in breast cancer treatment, identification and validation of novel resistance determinants is important to improve treatment efficacy and patient outcome. In our previous work we have found that AGR2 expression is elevated rather than inhibited in response to tamoxifen, thus we have evaluated the function of AGR2 during anti-hormone therapy. Our in vitro results clearly showed that AGR2 promotes viability of cells exposed to tamoxifen. Consequently AGR2 activation through the ER was confirmed by chromatin immunoprecipitation and reporter assays (3).

To reveal if AGR2 expression correlates with patient outcome or just mirrors hormonal levels in particular patients, we have determined the AGR2 expression in Tru-Cut needle biopsies from tamoxifen treated postmenopausal breast cancer patients. We found that AGR2 mRNA levels are inversely associated with primary treatment response (p=0.0011) and progression free survival (p=0.0366) indicating that elevated AGR2 expression predicts decreased efficacy of tamoxifen treatment. From this perspective, AGR2 is a potential predictive biomarker enabling selection of an optimal algorithm for adjuvant hormonal therapy in postmenopausal ER-positive breast cancer patients.

What is interesting, AGR2 expression could be less frequently detected also in estrogen receptor negative breast carcinomas. Analysis of consecutive group of breast tumors revealed that except estrogen receptor positive cases, AGR2 expression is associated with the HER2 molecular subtype especially, indicating that HER2 overexpression may influence AGR2 levels. These data are consistent with our recently published work showing involvement of PDPK1-AKT signaling pathway in regulation of AGR2 expression (4). Taken together it seems that apart from direct control of AGR2 expression by estrogen receptors, alternative pathway(-s) inclusive HER2 and AKT could be involved in regulation of AGR2 expression.

This work was supported by GACR P301/13/00956S, IGA NT/13794-4/2012 and RECAMO CZ.1.05/2.1.00/03.0101 (from European Regional Development Fund).

References

1. Katzenellenbogen BS, Frasor J. Therapeutic targeting in the estrogen receptor hormonal pathway. Semin Oncol 2004;31:28-38.

2. Ghayad SE, Vendrell JA, Ben Larbi S, Dumontet C, Bieche I, Cohen PA. Endocrine resistance associated with activated ErbB system in breast cancer cells is reversed by inhibiting MAPK or PI3K/Akt signaling pathways. Int J Cancer 2010;126:545-62.

3. Hrstka R, Nenutil R, Fourtouna A, Maslon MM, Naughton C, Langdon S, et al. The pro-metastatic protein anterior gradient-2 predicts poor prognosis in tamoxifen-treated breast cancers. Oncogene 2010;29:4838-47.

4. Hrstka R, Murray E, Brychtova V, Fabian P, Hupp TR, Vojtesek B. Identification of an AKT-dependent signalling pathway that mediates tamoxifen-dependent induction of the pro-metastatic protein anterior gradient-2. Cancer Lett 2013;333:187-93.

Citation Format: Roman Hrstka, Veronika Brychtova, Rudolf Nenutil, Pavel Fabian, Borek Vojtesek. Dissecting the role of AGR2 in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A120.