Although Inflammatory Breast Cancer (IBC) is a rare and an aggressive type of locally advanced breast cancer with a generally worst prognosis, little work has been done in identifying the status of non-genomic signaling in the invasiveness of IBC. The present study was performed to explore the status of non-genomic signaling as affected by various estrogenic and anti-estrogenic agents in IBC cell lines SUM149 and SUM190. We have identified the presence of estrogen receptor α (ERα) variant, ERα36 in SUM149 and SUM190 cells. This variant as well as ERβ was present in a substantial concentration in IBC cells. The treatment with estradiol (E2), anti-estrogenic agents 4-hydroxytamoxifen and ICI 182780, ERβ specific ligand DPN and GPR30 agonist G1 led to a rapid activation of p-ERK1/2, suggesting the involvement of ERα36, ERβ and GPR30 in the non-genomic signaling pathway in these cells. We also found a substantial increase in the cell migration and invasiveness of SUM149 cells upon the treatment with these ligands. Both basal and ligand-induced migration and invasiveness of SUM149 cells were drastically reduced in the presence of MEK inhibitor U0126, implicating that the phosphorylation of ERK1/2 by MEK is involved in the observed motility and invasiveness of IBC cells. We also provide evidence for the upregulation of p-ERK1/2 through immunostaining in IBC patient samples. These findings suggest a role of non-genomic signaling through the activation of p-ERK1/2 in the hormonal dependence of IBC by a combination of estrogen receptors. These findings only explain the failure of traditional anti-estrogen therapies in ER-positive IBC which induces the non-genomic signaling, but also opens newer avenues for design of modified therapies targeting these estrogen receptors.
References
[1]
Anderson WF, Schairer C, Chen BE, Hance KW, Levine PH (2005) Epidemiology of inflammatory breast cancer (IBC). Breast Dis 22: 9–23.
[2]
Hance KW, Anderson WF, Devesa SS, Young HA, Levine PH (2005) Trends in inflammatory breast carcinoma incidence and survival: The Surveillance, Epidemiology, and End Results program at the National Cancer Institute. J Natl Cancer Inst 97: 966–975.
[3]
Kleer CG, van Golen KL, Merajver SD (2000) Molecular biology of breast cancer metastasis. Inflammatory breast cancer: clinical syndrome and molecular determinants. Breast Cancer Res 2: 423–429.
[4]
Dirix LY, Van Dam P, Prové A, Vermeulen PB (2006) Inflammatory breast cancer: current understanding. Curr Opin Oncol 18: 563–571.
[5]
Merajver SD, Weber BL, Cody R, Zhang D, Strawderman M, et al. (1997) Breast conservation and prolonged chemotherapy for locally advanced breast cancer: the University of Michigan experience. J Clin Oncol 15: 2873–2881.
[6]
Abner AL, Recht A, Eberlein T, Come S, Shulman L, et al. (1993) Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 11: 44–48.
[7]
Hortobagyi GN, Ames FC, Buzdar AU, Kau SW, McNeese MD, et al. (1988) Management of stage III primary breast cancer with primary chemotherapy, surgery and radiation therapy. Cancer 62: 2507–2516.
[8]
Van Golen KL, Davies S, Wu ZF, Wang Y, Bucana CD, et al. (1999) A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype. Clin Cancer Res 5: 2511–2519.
[9]
Kleer CG, Zhang Y, Pan Q, van Golen KL, Wu ZF, et al. (2002) WISP3 is a novel tumor suppressor gene of inflammatory breast cancer. Oncogene 21: 3172–3180.
[10]
Kleer CG, Zhang Y, Pan Q, Gallagher G, Wu M, et al. (2004) WISP3 and RhoC guanosine triphosphatase cooperate in the development of inflammatory breast cancer. Breast Cancer Res 6: 110–115.
[11]
Van den Eynden GG, Van Laere SJ, Van der Auwera I, Merajver SD, Van Marck EA, et al. (2006) Overexpression of caveolin-1 and -2 in cell lines and in human samples of inflammatory breast cancer. Breast Cancer Res Treat 95: 219–228.
[12]
Charafe-Jauffret E, Tarpin C, Viens P, Bertucci F (2008) Defining the Molecular Biology of Inflammatory Breast Cancer. Semin Oncol 35: 41–50.
[13]
Wang Z, Zhang X, Shen P, Loggie BW, Chang Y, et al. (2005) Identification, cloning, and expression of human estrogen receptor-alpha36, a novel variant of human estrogen receptor-alpha66. Biochem Biophys Res Commun 336: 1023–1027.
[14]
Zou Y, Ding L, Coleman M, Wang Z (2009) Estrogen receptor-alpha (ER-alpha) suppresses expression of its variant ER-alpha36. FEBS Letters 583: 1368–1374.
[15]
Wang Z, Zhang X, Shen P, Loggie BW, Chang Y, et al. (2006) A variant of estrogen receptor-{alpha}, hER-{alpha}36: transduction of estrogen- and antiestrogen dependent membrane-initiated mitogenic signaling. Proc Natl Acad Sci U S A 103: 9063–9068.
[16]
Lin SL, Yan LY, Liang XW, Wang ZB, Wang ZY, et al. (2009) A novel variant of ER-alpha, ER-alpha36 mediates testosterone-stimulated ERK and Akt activation in endometrial cancer Hec1A cells. Reprod Biol Endocrinol 7: 102–109.
[17]
Carmeci C, Thompson DA, Ring HZ, Francke U, Weigel RJ (1997) Identification of a gene (GPR30) with homology to the G protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer. Genomics 45: 607–617.
[18]
Filardo E, Quinn J, Pang Y, Graeber C, Shaw S, et al. (2007) Activation of the novel estrogen receptor G protein-coupled Receptor 30 (GPR30) at the Plasma Membrane. Endocrinology 148: 3236–3245.
[19]
Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER (2005) A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307: 1625–1630.
[20]
Fraser SP, Ozerlat-Gunduz I, Onkal R, Diss JK, Latchman DS, et al. (2010) Estrogen and non-genomic upregulation of voltage-gated Na(+) channel activity in MDA-MB-231 human breast cancer cells: role in adhesion. J Cell Physiol 224: 527–539.
[21]
He YY, Cai B, Yang YX, Liu XL, Wan XP (2009) Estrogenic G protein-coupled receptor 30 signaling is involved in regulation of endometrial carcinoma by promoting proliferation, invasion potential, and interleukin-6 secretion via the MEK/ERK mitogen-activated protein kinase pathway. Cancer Sci 100: 1051–1061.
[22]
Ignatov A, Ignatov T, Roessner A, Costa SD, Kalinski T (2010) Role of GPR30 in the mechanisms of tamoxifen resistance in breast cancer MCF-7 cells. Breast Cancer Res Treat 123: 87–96.
[23]
Kang L, Zhang X, Xie Y, Tu Y, Wang D, et al. (2010) Involvement of estrogen receptor variant ER-{alpha}36, not GPR30, in nongenomic estrogen signaling. Mol. Endocrinol 24: 709–721.
[24]
Moriarty K, Kim KH, Bender JR (2006) Estrogen Receptor-Mediated Rapid Signaling. Endocrinology 147: 5557–5563.
[25]
Nguyen DM, Sam K, Tsimelzon A, Li X, Wong H, et al. (2006) Molecular heterogeneity of inflammatory breast cancer: a hyperproliferative phenotype. Clin Cancer Res 12: 5047–5054.
[26]
Jaiyesimi IA, Buzdar AU, Hortobagyi G (1992) Inflammatory breast cancer: a review. J Clin Oncol 10: 1014–1024.
[27]
McCarthy NJ, Yang X, Linnoila IR, Merino MJ, Hewitt SM, et al. (2002) Microvessel density, expression of estrogen receptor alpha, MIB-1, p53, and c-erbB-2 in inflammatory breast cancer. Clin Cancer Res 8: 3857–3862.
[28]
Lee LM, Cao J, Deng H, Chen P, Gatalica Z, et al. (2008) ER-alpha36, a novel variant of ER-alpha, is expressed in ER-positive and -negative human breast carcinomas. Anticancer Res 28: 479–483.
[29]
Deng H, Huang X, Fan J, Wang L, Xia Q, et al. (2010) A variant of estrogen receptor-alpha, ER-alpha36 is expressed in human gastric cancer and is highly correlated with lymph node metastasis. Oncol Rep 24: 171–176.
[30]
Zhang XT, Kang LG, Ding L, Vranic S, Gatalica Z, et al. (2011) A positive feedback loop of ER-α36/EGFR promotes malignant growth of ER-negative breast cancer cells. Oncogene 30: 770–780.
[31]
Madeo A, Maggiolini M (2010) Nuclear alternate estrogen receptor GPR30 mediates 17beta-estradiol-induced gene expression and migration in breast cancer-associated fibroblasts. Cancer Res 70: 6036–6046.
[32]
Ohshiro K, Rayala SK, Williams MD, Kumar R, El-Naggar AK (2006) Biological role of estrogen receptor beta in salivary gland adenocarcinoma cells. Clin Cancer Res 12: 5994–5999.
[33]
Zhang G, Liu X, Farkas AM, Parwani AV, Lathrop KL, et al. (2009) Estrogen receptor beta functions through nongenomic mechanisms in lung cancer cells. Mol Endocrinol 23: 146–156.
[34]
Huang GS, Gunter MJ, Arend RC, Li M, Arias-Pulido H, et al. (2010) Co-expression of GPR30 and ERbeta and their association with disease progression in uterine carcinosarcoma. Am J Obstet Gynecol 203(242): e1–5.
[35]
Plante BJ, Yuan L, Lessey BA, Young SL (2008) Regulation and signaling of the membrane estrogen receptor, GPR30, in human endometrial cells. Reprod Sci 15: 70A.
[36]
Lin SL, Yan LY, Zhang XT, Yuan J, Li M, et al. (2010) ER-alpha36, a variant of ER-alpha, promotes tamoxifen agonist action in endometrial cancer cells via the MAPK/ERK and PI3K/Akt pathways. PLoS One 5: e9013.
[37]
Vivacqua A, Bonofiglio D, Albanito L, Madeo A, Rago V, et al. (2006) 17beta-estradiol, genistein, and 4-hydroxytamoxifen induce the proliferation of thyroid cancer cells through the g protein-coupled receptor GPR30. Mol Pharmacol 70: 1414–1423.
[38]
Vivacqua A, Bonofiglio D, Recchia AG, Musti AM, Picard D, et al. (2006) The G protein-coupled receptor GPR30 mediates the proliferative effects induced by 17beta-estradiol and hydroxytamoxifen in endometrial cancer cells. Mol Endocrinol 20: 631–646.
[39]
Li Y, Birnbaumer L, Teng CT (2010) Regulation of ERRalpha gene expression by estrogen receptor agonists and antagonists in SKBR3 breast cancer cells: differential molecular mechanisms mediated by g protein-coupled receptor GPR30/GPER-1. Mol Endocrinol 24(5): 969–980.
[40]
Paradiso A, Tommasi S, Brandi M, Marzullo F, Simone G, et al. (1989) Cell kinetics and hormonal receptor status in inflammatory breast carcinoma. Comparison with locally advanced disease. Cancer 64: 1922–1927.
[41]
Van den Eynden GG, Van der Auwera I, Van Laere S, Colpaert CG, van Dam P, et al. (2004) Validation of a tissue microarray to study differential protein expression in inflammatory and non-inflammatory breast cancer. Breast Cancer Res Treat 85: 13–22.
[42]
Lappano R, Rosano C, De Marco P, De Francesco EM, Pezzi V, et al. (2010) Estriol acts as a GPR30 antagonist in estrogen receptor-negative breast cancer cells. Mol Cell Endocrinol 320: 162–170.
