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Estrogen Receptor B Represses Akt Signaling Lindberg et al. Breast Cancer Research 2011, 13:R43 http://breast-cancer-research.com/content/13/2/R43 RESEARCHARTICLE Open Access Estrogen receptor b represses Akt signaling in breast cancer cells via downregulation of HER2/ HER3 and upregulation of PTEN: implications for tamoxifen sensitivity Karolina Lindberg1, Luisa A Helguero2, Yoko Omoto1, Jan-Åke Gustafsson1,3 and Lars-Arne Haldosén1* Abstract Introduction: The inhibition of estrogen receptor (ER) a action with the ER antagonist tamoxifen is an established treatment in the majority of breast cancers. De novo or acquired resistance to this therapy is common. Expression of ERb in breast tumors has been implicated as an indicator of tamoxifen sensitivity. The mechanisms behind this observation remain largely uncharacterized. In the present study, we investigated whether ERb can modulate pathways implicated in endocrine resistance development. Methods: T47-D and MCF-7 ERa-expressing breast cancer cells with tetracycline-regulated expression of ERb were used as a model system. Expression levels and activity of known regulators of endocrine resistance were analyzed by performing quantitative polymerase chain reaction assays, Western blot analysis and immunostaining, and sensitivity to tamoxifen was investigated by using a cell proliferation kit. Results: Expression of ERb in ERa-positive T47-D and MCF-7 human breast cancer cells resulted in a decrease in Akt signaling. The active form of an upstream regulator of Akt, proto-oncogene c-ErbB-2/receptor tyrosine kinase erbB-3 (HER2/HER3) receptor dimer, was also downregulated by ERb. Furthermore, ERb increased expression of the important inhibitor of Akt, phosphatase and tensin homologue deleted on chromosome 10 (PTEN). Importantly, ERb expression increased the sensitivity of these breast cancer cells to tamoxifen. Conclusions: Our results suggest a link between expression of ERb and endocrine sensitivity by increasing PTEN levels and decreasing HER2/HER3 signaling, thereby reducing Akt signaling with subsequent effects on proliferation, survival and tamoxifen sensitivity of breast cancer cells. This study supports initiatives to further investigate whether ERb presence in breast cancer samples is an indicator for endocrine response. Current therapies in ERa-positive breast cancers aim to impair ERa activity with antagonists or by removal of endogenous estrogens with aromatase inhibitors. Data from this study could be taken as indicative for also using ERb as a target in selected groups of breast cancer. Introduction ERb, have been identified [3]. ERa plays an important Approximately two-thirds of breast cancers express role in the proliferation and progression of breast can- estrogen receptors (ERs) and initially require estrogen to cer, whereas a distinct function of ERb in breast cancer grow, and are therefore treated with ER antagonists, initiation and development has not yet been clearly such as tamoxifen, or by depletion of endogenous estro- established. In in vitro settings, ERb inhibits prolifera- gens with aromatase inhibitors [1,2]. Two ERs, ERa and tion, migration and invasion of breast cancers cells [4-9] as well as the growth of breast tumor xenografts [10]. ERa is the marker of choice to decide endocrine treat- * Correspondence: [email protected] ment of breast cancer. However, in the case of tamoxi- 1Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Blickagången 6, S-141 83 Huddinge, Sweden fen treatment, despite the initial response to the Full list of author information is available at the end of the article © 2011 Lindberg et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lindberg et al. Breast Cancer Research 2011, 13:R43 Page 2 of 13 http://breast-cancer-research.com/content/13/2/R43 therapy, one-third of patients will acquire resistance and associated with poor disease outcome [41-44]. even though their ERa status may remain unchanged PTEN antagonizes PI3K activity by dephosphorylating [11]. ERb has also been considered a marker of endo- PIP3, resulting in lower levels of active Akt [45]. crine response. Lower expression of ERb is found in The goal of this study was to investigate whether tamoxifen-resistant tumors, and high levels of ERb are ERb1 (referred to hereinafter as ERb) has any effect on sometimes associated with a better clinical outcome in the RTK/PI3K/Akt signaling pathway and thereby repre- ERa-expressing breast tumors [12]. However, some stu- sents a regulator of tamoxifen sensitivity. We show that dies have indicated that in high-grade, ERa-negative, in ERa-positive breast cancer cells, expression of ERb node-positive breast tumors, ERb presence appears to reduced Akt activation through downregulation of be a marker related to a more aggressive breast cancer HER2/HER3 signaling and upregulation of PTEN and, [13]. importantly, increased sensitivity to tamoxifen. ERb has Breast tumors overexpressing receptor tyrosine kinases sometimes been suggested as a predictor of endocrine (RTKs) are less likely to benefit from tamoxifen treat- response; however, the mechanisms underlying this ment [14-17]. Receptor tyrosine protein kinase erbB-3 response are still unknown. Here we suggest a link (HER3) and proto-oncogene c-ErbB-2 (HER2) are mem- between expression of ERb and endocrine sensitivity. bers of the epidermal growth factor receptor (EGFR) family. HER3 lacks intrinsic kinase activity and relies on Materials and methods heterodimerization with other members of the EGFR Cell cultures family for transduction of signals. There is growing T47-D cells with tetracycline-regulated expression of awareness of the importance of HER2/HER3 heterodi- ERb485 (T47-DERb) [4] were routinely grown not mer formation in breast cancer progression, where coex- expressing ERb (-ERb) in RPMI 1640 medium (Invitro- pression of HER2 and HER3 has been shown to be a gen, Paisley, United Kingdom) supplemented with 5% poor prognostic indicator associated with resistance to heat-inactivated fetal bovine serum (FBS) (Invitrogen), endocrine therapy and to HER tyrosine kinase inhibitors 1% penicillin-streptomycin (Invitrogen) and 10 ng/mL [18-22]. The majority of HER2-positive tumors are doxycycline (Sigma, Stockholm, Sweden). For experi- strongly positive for HER3 [18], which is also seen in ments, cells were grown for 24 to 168 hours prior to mouse models of breast cancers, where high expression analysis in phenol red-free RPMI 1640 medium supple- of HER2 is commonly associated with activated and mented with 2% heat-inactivated FBS, 1% penicillin- overexpressed HER3 [23]. Furthermore, inhibition of streptomycin, 10 ng/mL -ERb or 0.01 ng/mL doxycy- HER2 correlates with reduction in HER3 phosphoryla- cline +ERb in the presence of vehicle alone, ethanol tion [24] and, correspondingly, inhibition of HER3 and/or dimethyl sulfoxide (Sigma), or in 10 nM 2,3-bis reduces phosphorylation of HER2 and abrogates HER2- (4-hydroxy-phenyl)-propionitrile (DPN) (Tocris, Bristol, mediated tamoxifen resistance [25]. United Kingdom), 10 nM 4,4’,4"-(4-propyl-[1H]-pyra- Phosphatidylinositol 3-kinase (PI3K) promotes genera- zole-1,3,5-triyl)trisphenol (PPT) (Tocris), 10 nM 17b- tion of phosphatidylinositol (3,4,5)-triphosphate (PIP3), estradiol (E2) (Sigma), 10 nM 7-bromo-2-(4-hydroxy- which leads to phosphorylation and activation of the phenyl)-1,3-benzoxazol-5-ol (WAY) (Tocris), 100 nM serine/threonine kinase Akt. The PI3K/Akt pathway ICI 182, 789 (ICI) (Tocris) or 100 to 1,000 nM 4- plays important roles in regulating cell proliferation, hydroxy-tamoxifen (4-OH-T) (Sigma). MCF-7 breast growth, apoptosis and motility. Increased activity due to cancer cells with tetracycline-regulated expression of genetic changes is frequently seen in breast cancer, ERb485 were treated in a similar manner. T47-DPBI resulting in tumor progression, metastases and resis- cells (Mock) were used as controls. tance to endocrine treatment [26-29]. Mutation of the PIK3CA gene, which encodes the p110a catalytic subu- Quantitative real-time polymerase chain reaction assays nit of PI3K, leads to activation of Akt and is found in Cells were grown in six-well tissue culture plates for 24 18% to 40% of human breast cancers [30-32]. Stimula- to 96 hours and lysed in TRIzol reagent (Invitrogen), tion of RTKs also activates Akt [33-35], and overexpres- then RNA was extracted and cDNA was synthesized as sion of HER2 is linked to elevated Akt activities [36-38]. described previously [46]. Quantitative real-time poly- In ERa-positive breast cancers treated with tamoxifen, merase reaction assays (qRT-PCR) were performed with detection of activated Akt at diagnosis has been shown SYBR Green PCR Master Mix in an ABI PRISM 7500 to correlate to decreased overall survival [39]. (Applied Biosystems, Foster City, USA). The following Constitutive active Akt is also associated with loss of primers were used: 18S forward 5’-CCTGCGGCTTAA- phosphatase and tensin homologue deleted on chromo- TTTGACTCA-3’, reverse 5’-AGCTATCAATCTGT- some 10 (PTEN) expression [40]. PTEN is a tumor sup- CAATCCTGTCC-3’; ERb forward 5’-ACTTGCTG- pressor whose expression is often lost in breast cancers AACGCCGTGACC-3’,reverse5’-CAGATGTTCCA- Lindberg et al. Breast Cancer Research 2011, 13:R43 Page 3 of 13 http://breast-cancer-research.com/content/13/2/R43
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