Abstract
Many cases of breast cancer show loss of estrogen receptor (ER) α expression, which leads to unresponsiveness to antihormonal treatment even though there is no loss of the structurally and biochemically similar ER β. ER activity is positively and negatively regulated by transcriptional regulators such as histone deacetylase (HDAC), which is known to be a negative ER regulator. Here, we evaluated using ER β as an alternative target for tamoxifen therapy by treating ER α-negative, β-positive breast cancer cells with the HDAC inhibitor trichostatin A (TSA), and testing whether tamoxifen responsiveness increased following upregulation of ER β. TSA enhanced the overall ER transcriptional activity in these cells, as visualized by estrogen response element-regulated reporter and the expression of progesterone receptor, a known ER target, without ER α restoration. Additionally, TSA induced the expression and nuclear translocation of ER β but not α, suggesting that these actions leading to increase of ER transcriptional activity are mediated through ER β rather than α. Furthermore, following treatment with TSA, the formerly unresponsive MDA-MB-231 and Hs578T breast cancer cells became responsive to tamoxifen. However, reduction of ER β expression by short interfering RNA abrogated this TSA-induced sensitization effect in these cells. Together, these results show that the HDAC inhibitor TSA sensitized ER α-negative, antihormone-unresponsive breast cancer cells to tamoxifen treatment possibly by upregulating ER β activity.
Similar content being viewed by others
References
Acevedo ML and Kraus WL . (2003). Mol. Cell. Biol., 23, 335–348.
An J, Ribeiro RCJ, Webb P, Gustafsson J-A, Kushner PJ, Baxter JD and Leitman DC . (1999). Proc. Natl. Acad. Sci. USA, 96, 15161–15166.
Bieche I, Parfait B, Laurendeau I, Girault I, Vidaud M and Lidereau R . (2001). Oncogene, 20, 8109–8115.
Bovenzi V and Momparler RL . (2001). Cancer Chemother. Pharmacol., 48, 71–76.
Carmichael J, DeGraff WG, Gazdar AF, Minna JD and Mitchell JB . (1987). Cancer Res., 47, 936–942.
Brummelkamp TR, Bernards R and Agami R . (2002). Science, 296, 550–553.
Chang J, Powles TJ, Allred DC, Ashley SE, Makris A, Gregory RK, Osborne CK and Dowsett M . (2000). Clin. Cancer Res., 6, 616–621.
Couse JF and Korach KS . (1999). Endocr. Rev., 20, 358–417.
Fan S, Ma YX, Wang C, Yuan RQ, Meng Q, Wang JA, Erdos M, Goldberg ID, Webb P, Kushner PJ, Pestell RG and Rosen EM . (2002). Cancer Res., 62, 141–151.
Fan S, Wang J, Yuan R, Ma Y, Meng Q, Erdos MR, Pestell RG, Yuan F, Auborn KJ, Goldberg ID and Rosen EM . (1999). Science, 284, 1354–1356.
Ghoshal K, Datta J, Majumder S, Bai S, Dong X, Parthun M and Jacob ST . (2002). Mol. Cell. Biol., 22, 8302–8319.
Hager GL, Lim CS and Elbi CBaumann CT . (2000). J. Steroid Biochem. Mol. Biol., 30, 249–254.
Hall JM and McDonnell DP . (1999). Endocrinology, 140, 5566–5578.
Hedden A, Muller V and Jensen EV . (1995). Ann. NY Acad. Sci., 761, 109–120.
Jensen EV, Cheng G, Palmieri C, Saji S, Makela S, Van Noorden S, Wahlstrom T, Warner M, Coombes RC and Gustafsson JA . (2001). Proc. Natl. Acad. Sci. USA, 98, 15197–15202.
Jordan VC . (2001). Ann. NY Acad. Sci., 949, 72–79.
Jung DJ, Lee SK and Lee JW . (2001). J. Biol. Chem., 276, 37280–37283.
Kaaks R, Lukanova A and Kurzer MS . (2002). Cancer Epidemiol. Biomarkers Prev., 11, 1531–1543.
Kawata M . (2001). Arch. Histol. Cytol., 64, 353–368.
Kim MY, Hsiao S and Kraus WL . (2001). EMBO J., 20, 6084–6094.
Kumar R, Wang RA, Mazumdar A, Talukder AH, Mandal M, Yang Z, Bagheri-Yarmand R, Sahin A, Hortobagyi G, Adam L, Barnes CJ and Vadlamudi RK . (2002). Nature, 418, 654–657.
Levenson AS, Svoboda KM, Pease KM, Kaiser SA, Chen B, Simons LA, Jovanovic BD, Dyck PA and Jordan VC . (2002). Cancer Res., 62, 4419–4426.
Liu M-M, Albaneses C, Anderson CM, Hilty K, Webb P, Uh RM, Price RH, Pestell RG and Kushner PJ . (2002). J. Biol. Chem., 277, 24353–24360.
Macaluso M, Cinti C, Russo G, Russo A and Giordano A . (2003). Oncogene, 22, 3511–3517.
Mandlekar S and Kong A-N . (2001). Apoptosis, 6, 469–477.
Matsuda K, Ochiai I, Nishi M and Kawata M . (2002). Mol. Endocrinol., 16, 2215–2230.
Mazumdar A, Wang RA, Mishra SK, Adam L, Bagheri-Yarmand R, Mandal M, Vadlamudi RK and Kumar R . (2001). Nat. Cell Biol., 3, 30–37.
McDonnell DP and Norris JD . (2002). Science, 296, 1642–1644.
Nilsson S and Gustafsson JA . (2000). Breast Cancer Res., 2, 360–366.
Noh EJ and Lee J-S . (2003). Biochem. Biophys. Res. Commun., 310, 267–273.
Norris JD, Fan D, Sherk A and McDonnell DP . (2002). Mol. Endocrinol., 16, 459–468.
Paech K, Webb P, Kuiper GGJ, Nilsson S, Gustafsson J-A, Kushner PJ and Scanlan TS . (1999). Science, 277, 1508–1510.
Palmieri C, Cheng GJ, Saji S, Zelada-Hedman M, Warri A, Weihua Z, Van Noorden S, Wahlstrom T, Coombes RC, Warner M and Gustafsson J-A . (2002). Endocr. Relat. Cancer, 9, 1–13.
Park W-C and Jordan VC . (2002). Trends Mol. Med., 8, 82–87.
Powles TJ . (2002). Nat. Rev. Cancer, 2, 787–794.
Scott GK, Marden C, Xu F, Kirk L and Benz CC . (2002). Mol. Cancer Ther., 1, 385–392.
Shi Y, Downes M, **e W, Kao HY, Ordentlich P, Tsai CC, Hon M and Evans RM . (2001). Genes Dev., 15, 1140–1151.
Sun JM, Chen HY and Davie JR . (2001). J. Biol. Chem., 276, 49435–49442.
Weihua Z, Lathe R, Warner M and Gustafsson JA . (2002). Proc. Natl. Acad. Sci. USA, 99, 13589–13594.
Yanagisawa J, Kitagawa H, Yanagida M, Wada O, Ogawa S, Nakagomi M, Oishi H, Yamamoto Y, Nagasawa H, McMahon SB, Cole MD, Tora L, Takahashi N and Kato S . (2002). Mol. Cell, 9, 553–562.
Yang X, Ferguson AT, Nass SJ, Phillips DL, Butash KA, Wang SM, Herman JG and Davidson NE . (2000). Cancer Res., 60, 6890–6894.
Yang X, Phillips DL, Ferguson AT, Nelson WG, Herman JG and Davidson NE . (2001). Cancer Res., 61, 7025–7029.
Acknowledgements
We thank members of the Lee laboratory for comments on the manuscript and Drs Hyunsook Lee and Reuven Agami for the gift of pSUPER plasmid. This work was supported by grants from National Cancer Center, from Korea Research Foundation (KRF-2000-015-DP0371) and from Cancer Mestastasis Research Center.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jang, E., Lim, SJ., Lee, E. et al. The histone deacetylase inhibitor trichostatin A sensitizes estrogen receptor α-negative breast cancer cells to tamoxifen. Oncogene 23, 1724–1736 (2004). https://doi.org/10.1038/sj.onc.1207315
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1207315
- Springer Nature Limited
Keywords
This article is cited by
-
Co-inhibition of mTORC1, HDAC and ESR1α retards the growth of triple-negative breast cancer and suppresses cancer stem cells
Cell Death & Disease (2018)
-
HDAC 1 and 6 modulate cell invasion and migration in clear cell renal cell carcinoma
BMC Cancer (2016)
-
Synergistic effects of combined treatment with histone deacetylase inhibitor suberoylanilide hydroxamic acid and TRAIL on human breast cancer cells
Scientific Reports (2016)
-
Combined histone deacetylase inhibition and tamoxifen induces apoptosis in tamoxifen-resistant breast cancer models, by reversing Bcl-2 overexpression
Breast Cancer Research (2015)
-
The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer
Oncogenesis (2015)