JCT  Vol.6 No.9 , September 2015
Promestriene Affects GREB1 Expression in Estrogen Sensitive Breast Cancer Cells
Abstract: Promestriene (3-propyl ethyl, 17B-methyl estradiol) is a synthetic estrogen analogue with reported minimal systemic absorption which has been suggested for topical treatment of vaginal atrophy. Promestriene’s ability to stimulate proliferation and estrogen responsive gene expression was analyzed in estrogen receptor (ER+) positive breast cancer cell lines MCF-7, T-47D, and BT-474 using CFSE flow cytometric analysis, and quantitative RT-PCR analysis of GREB1 RNA expression, an estrogen responsive gene involved in estrogen receptor alpha expression. In estrogen replete conditions, Promestriene did not stimulate proliferation even at high concentrations (100,000 pg/ml). However, anti-estradiol depletion allowed low dose Promestriene (2 - 10 pg/ml) to stimulate GREB1 expression in all three cell lines at levels equal to that induced by estradiol (BT-474) or significantly higher than estradiol (MCF7 and T-47D). These findings suggest that Promestriene has the potential to support estrogen like cell signaling, a possible contraindication for use in treatment of vaginal atrophy associated with breast cancer aromatase inhibitor therapy.
Cite this paper: Almodovar, A. , Zhu, X. , Litherland, S. , Decker, D. (2015) Promestriene Affects GREB1 Expression in Estrogen Sensitive Breast Cancer Cells. Journal of Cancer Therapy, 6, 767-772. doi: 10.4236/jct.2015.69084.

[1]   Kohler, B.A., Sherman, R.L., Howlader, N., Jemal, A., Ryerson, A.B., Henry, K.A., Boscoe, F.P., Cronin, K.A., Lake, A., Noone, A.-M., Henley, S.J., Eherman, C.R., Anderson, R.N. and Penberthy, L. (2015) Annual Report to the Nation on the Status of Cancer, 1975-2011, Featuring Incidence of Breast Cancer Subtypes by Race/Ethnicity, Poverty, and State. Journal of the National Cancer Institute, Online 30 March 2015.

[2]   Williams, C. and Lin, C.-Y. (2013) Oestrogen Receptors in Breast Cancer: Basic Mechanisms and Clinical Implications. Ecancermedicalscience, 7, 370-382.

[3]   Munster, P.N., Thurn, K.T., Thomas, S., Raha, P., Lacevic, M., Miller, A., Melisko, M., Ismail-Khan, R., Rugo, H., Moasser, M. and Minton, S.E. (2011) A Phase II Study of the Histone Deacetylase Inhibitor Vorinstat Combined with Tamoxifen for the Treatment of Patients with Hormone Therapy-Resistant Breast Cancer. British Journal of Cancer, 104, 1828-1835.

[4]   Shen, C., Huang, Y., Liu, Y., Wang, G., Zhao, Y., Wang, Z., Ten, M., Wang, Y., Flockhart, D.A., Skaar, T.C., Yan, P., Nephew, K.P., Huang, T.H.M. and Li, L. (2011) A Modulated Empirical Bayes Model for Identifying Topological and Temporal Estrogen Receptor Alpha Regulatory Networks in Breast Cancer. BMC Systems Biology, 5, 67-83.

[5]   Kubo, M., Kanaya, N., Petrossian, K., Ye, J., Warden, C., Liu, Z., Nishimura, R., Osako, T., Okido, M., Shimada, K., Takahashi, M., Chu, P., Yuan, Y.-C. and Chen, S. (2013) Inhibition of the Proliferation of Acquired Aromatase Inhibitor-Resistant Breast Cancer Cells by Histone Deacetylase Inhibitor LBH589 (Panobinostat). Breast Cancer Research and Treatment, 137, 93-107.

[6]   Del Pup, L. (2012) Management of Vaginal Dryness and Dyspareunia in Estrogen Sensitive Cancer Patients. Gynecological Endocrinology, 28, 740-745.

[7]   Santos, I. and Clissold, S. (2010) Urogenital Disorders Associated with Estrogen Deficiency: The Role of Promestriene as Topical Oestrogen Therapy. Gynecological Endocrinology, 26, 644-651.

[8]   Wolff, J.-P., Cachelou, R. and Gueritee, N. (1982) Absence of Systemic Hormonal Effects in an Oestradiol Diether Topically Active on the Vaginal Mucosa. Maturitas, 4, 239-246.

[9]   Howell, A., Clarke, R.B., Evans, G., Bundred, N., Cuzick, J., Santen, R. and Allred, C. (2007) Estrogen Deprivation for Breast Cancer Prevention. Recent Results in Cancer Research, 174, 151-167.

[10]   Wills, S., Ravipati, A., Venuturumilli, P., Kesge, C., Folkerd, E., Dowsett, M., Hayes, D.F. and Decker, D.A. (2012) Effects of Vaginal Estrogens on Serum Estradiol Levels in Postmenopausal Breast Cancer Survivors and Women at Risk of Breast Cancer Taking an Aromatase Inhibitor or a Selective Estrogen Receptor Modulator. Journal of Oncology Practice, 11, 144-148.

[11]   Fiers, T., Casetta, B., Bernaert, B., Vandersypt, E., Debock, M. and Kaufman, J.M. (2012) Development of a Highly Sensitive Method for the Quantification of Estrone and Estradiol in Serum by Liquid Chromatography Tandem Mass Spectrometry without Derivatization. Journal of Chromatography B, 893-894, 57-62.

[12]   Rae, J.M., Johnson, M.D., Scheys, J.O., Cordero, K.E., Larios, J.M. and Lippman, M.E. (2005) GREB1 Is a Critical Regulator of Hormone Dependent Breast Cancer Growth. Breast Cancer Research and Treatment, 92, 141-149.

[13]   Mohammed, H., D’Santos, C., Serandour, A.A., Ali, H.R., Brown, G.D., Atkins, A., Rueda, O.M., Holmes, K.A., Theodorou, V., Robinson, J.L.L., Zwart, W., Saadi, A., Ross-Innes, C.S., Chin, S.-F., Menon, S., Stingl, J., Palmieri, C., Caldas, C. and Carroll, J.S. (2013) Endogenous Purification Reveals GREB1 as a Key Estrogen Receptor Regulatory Factor. Cell Reports, 3, 342-349.

[14]   Ghosh, M.G., Thompson, D.A. and Weigel, R.J. (2000) PDZK1 and GREB1 Are Estrogen-Regulated Genes Expressed in Hormone-Responsive Breast Cancer. Cancer Research, 60, 6367-6375.

[15]   Dunbier, A.K., Anderson, H., Ghazoui, Z., Folkerd, E.J., A’hern, R., Crowder, R.J., Hoog, J., Smith, I.E., Osin, P., Nerurkar, A., Parker, J.S., Perou, C.M., Ellis, M.J. and Dowsett, M. (2010) Relationship between Plasma Estradiol Levels and Estrogen-Responsive Gene Expression in Estrogen Receptor-Positive Breast Cancer in Postmenopausal Women. Journal of Clinical Oncology, 28, 1161-1167.

[16]   Zwart, W., Theodorou, V., Kok, M., Canisius, S., Linn, S. and Carroll, J.S. (2011) Oestrogen Receptor-Co-Factor-Chromatin Specificity in the Transcriptional Regulation of Breast Cancer. The EMBO Journal, 30, 4764-4776.

[17]   Liu, M., Wang, G., Gomez-Fernandez, C.R. and Guo, S. (2012) GREB1 Functions as a Growth Promoter and Is Modulated by IL6/STAT3 in Breast Cancer. PLoS ONE, 7, e46410.

[18]   Englert, N.A., Spink, B.C. and Spink, D.C. (2011) Persistent and Non-Persistent Changes in Gene Expression Result from Long-Term Estrogen Exposure of MCF-7 Breast Cancer Cells. The Journal of Steroid Biochemistry and Molecular Biology, 123, 140-150.

[19]   Meng, Q., Chen, X., Sun, L., Zhao, C., Sui, G. and Cai, L. (2011) Carbamazepine Promotes Her-2 Protein Degradation in Breast Cancer Cells by Modulating HDAC6 Activity and Acetylation. Molecular and Cellular Biochemistry, 348, 165-171.

[20]   Yardley, D.A., Ismail-Khan, R.R., Melichar, B., Lichinitser, M., Munster, P.N., Klein, P.M., Cruickshank, S., Miller, K.D., Lee, M.J. and Trepel, J.B. (2013) Randomized Phase II, Double-Blind, Placebo-Controlled Study of Exemestane with or without Entinostat in Postmenopausal Women with Locally Recurrent or Metastatic Estrogen Receptor-Positive Breast Cancer Progressing on Treatment with a Nonsteroidal Aromatase Inhibitor. Journal of Clinical Oncology, 31, 2128-2135.