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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 2/2017

01-01-2017 | Preclinical study

Downregulation of estrogen receptor and modulation of growth of breast cancer cell lines mediated by paracrine stromal cell signals

Authors: J. Huang, P. Woods, D. Normolle, J. P. Goff, P. V. Benos, C. J. Stehle, R. A. Steinman

Published in: Breast Cancer Research and Treatment | Issue 2/2017

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Abstract

Purpose

Breast cancers have a poorer prognosis if estrogen receptor expression was lost during recurrence. It is unclear whether this conversion is cell autonomous or whether it can be promoted by the microenvironment during cancer dormancy. We explored the ability of marrow-derived stromal cell lines to arrest co-cultured breast cancer cells and suppress estrogen receptor alpha (ER) expression during arrest, facilitating the emergence of estrogen-independent breast cancer clones.

Methods

Cancer cell growth, ER protein, microRNA, and mRNA levels were measured in breast cancer cell lines exposed to conditioned medium from marrow stromal lines in the presence and absence of estrogen and of signaling pathway modulators.

Results

We demonstrate that paracrine signaling from the stromal cell line HS5 downregulated ER in T47D and MCF7 breast cancer cells. This occurred at the mRNA level and also through decreased ER protein stability. Additionally, conditioned medium (CM) from HS5 arrested the breast cancer cells in G0/G1 in part through interleukin-1 (IL1) and inhibited cancer cell growth despite the activation of proliferative pathways (Erk and AKT) by the CM. Similar findings were observed for CM from the hFOB 1.19 osteoblastic cell line but not from two other fibroblastic marrow lines, HS27A and KM101. HS5-CM inhibition of MCF7 proliferation could not be restored by exogenous ER, but was restored by the IL1-antagonist IL1RA. In the presence of IL1RA, HS5-CM activation of AKT and Erk enabled the outgrowth of breast cancer cells with suppressed ER that were fulvestrant-resistant and estrogen-independent.

Conclusions

We conclude that marrow-derived stromal cells can destabilize estrogen receptor protein to convert the ER status of growth-arrested ER+ breast cancer cell lines. The balance between stromal pro- and anti-proliferative signals controlled the switch from a dormant phenotype to estrogen-independent cancer cell growth.
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Literature
1.
Hoefnagel LD, van de Vijver MJ, van Slooten HJ, Wesseling P, Wesseling J, Westenend PJ, Bart J, Seldenrijk CA, Nagtegaal ID, Oudejans J et al (2010) Receptor conversion in distant breast cancer metastases. Breast Cancer Res 12(5):R75CrossRefPubMedPubMedCentral
2.
Hoefnagel LD, Moelans CB, Meijer SL, van Slooten HJ, Wesseling P, Wesseling J, Westenend PJ, Bart J, Seldenrijk CA, Nagtegaal ID et al (2012) Prognostic value of estrogen receptor alpha and progesterone receptor conversion in distant breast cancer metastases. Cancer 118(20):4929–4935CrossRefPubMed
3.
Fehm T, Krawczyk N, Solomayer EF, Becker-Pergola G, Durr-Storzer S, Neubauer H, Seeger H, Staebler A, Wallwiener D, Becker S (2008) ERalpha-status of disseminated tumour cells in bone marrow of primary breast cancer patients. Breast Cancer Res 10(5):R76CrossRefPubMedPubMedCentral
4.
Ono M, Kosaka N, Tominaga N, Yoshioka Y, Takeshita F, Takahashi RU, Yoshida M, Tsuda H, Tamura K, Ochiya T (2014) Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci Signal 7(332):ra63CrossRefPubMed
5.
Ogba N, Manning NG, Bliesner BS, Ambler SK, Haughian JM, Pinto MP, Jedlicka P, Joensuu K, Heikkila P, Horwitz KB (2014) Luminal breast cancer metastases and tumor arousal from dormancy are promoted by direct actions of estradiol and progesterone on the malignant cells. Breast Cancer Res 16(6):489CrossRefPubMedPubMedCentral
6.
Zhou W, Slingerland JM (2014) Links between oestrogen receptor activation and proteolysis: relevance to hormone-regulated cancer therapy. Nat Rev Cancer 14(1):26–38CrossRefPubMed
7.
Macaluso M, Montanari M, Noto PB, Gregorio V, Bronner C, Giordano A (2007) Epigenetic modulation of estrogen receptor-α by pRb family proteins: a novel mechanism in breast cancer. Cancer Res 67(16):7731–7737CrossRefPubMed
8.
Dhasarathy A, Kajita M, Wade PA (2007) The transcription factor snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor-α. Mol Endocrinol 21(12):2907–2918CrossRefPubMedPubMedCentral
9.
Pan X, Zhou T, Tai YH, Wang C, Zhao J, Cao Y, Chen Y, Zhang PJ, Yu M, Zhen C et al (2011) Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer. Nat Med 17(6):708–714CrossRefPubMed
10.
Fan M, Bigsby RM, Nephew KP (2003) The NEDD8 pathway is required for proteasome-mediated degradation of human estrogen receptor (ER)-alpha and essential for the antiproliferative activity of ICI 182,780 in ERα-positive breast cancer cells. Mol Endocrinol 17(3):356–365CrossRefPubMed
11.
Nawaz Z, Lonard DM, Dennis AP, Smith CL, O’Malley BW (1999) Proteasome-dependent degradation of the human estrogen receptor. Proc Natl Acad Sci USA 96(5):1858–1862CrossRefPubMedPubMedCentral
12.
13.
Shah SH, Miller P, Garcia-Contreras M, Ao Z, Machlin L, Issa E, El-Ashry D (2015) Hierarchical paracrine interaction of breast cancer associated fibroblasts with cancer cells via hMAPK-microRNAs to drive ER-negative breast cancer phenotype. Cancer Biol Ther 16(11):1671–1681CrossRefPubMedPubMedCentral
14.
Pinzone JJ, Stevenson H, Strobl JS, Berg PE (2004) Molecular and cellular determinants of estrogen receptor α expression. Mol Cell Biol 24(11):4605–4612CrossRefPubMedPubMedCentral
15.
Sflomos G, Dormoy V, Metsalu T, Jeitziner R, Battista L, Scabia V, Raffoul W, Delaloye JF, Treboux A, Fiche M et al (2016) A preclinical model for ERα-positive breast cancer points to the epithelial microenvironment as determinant of luminal phenotype and hormone response. Cancer Cell 29(3):407–422CrossRefPubMed
16.
Roecklein BA, Torok-Storb B (1995) Functionally distinct human marrow stromal cell lines immortalized by transduction with the human papilloma virus E6/E7 genes. Blood 85(4):997–1005PubMed
17.
Iwata M, Sandstrom RS, Delrow JJ, Stamatoyannopoulos JA, Torok-Storb B (2014) Functionally and phenotypically distinct subpopulations of marrow stromal cells are fibroblast in origin and induce different fates in peripheral blood monocytes. Stem Cells Dev 23(7):729–740CrossRefPubMed
18.
Iwata M, Torok-Storb B, Wayner EA, Carter WG (2014) CDCP1 identifies a CD146 negative subset of marrow fibroblasts involved with cytokine production. PLoS ONE 9(10):e109304CrossRefPubMedPubMedCentral
19.
Marlow R, Honeth G, Lombardi S, Cariati M, Hessey S, Pipili A, Mariotti V, Buchupalli B, Foster K, Bonnet D et al (2013) A novel model of dormancy for bone metastatic breast cancer cells. Cancer Res 73(23):6886–6899CrossRefPubMed
20.
Cavnar SP, Rickelmann AD, Meguiar KF, Xiao A, Dosch J, Leung BM, Cai Lesher-Perez S, Chitta S, Luker KE, Takayama S et al (2015) Modeling selective elimination of quiescent cancer cells from bone marrow. Neoplasia 17(8):625–633CrossRefPubMedPubMedCentral
21.
FitzGerald TJ, Santucci MA, Harigaya K, Woda B, McKenna M, Sakakeeny MA, Pierce JH, Kase K, Holland CA, Greenberger JS (1988) Radiosensitivity of permanent human bone marrow stromal cell lines: effect of dose rate. Int J Radiat Oncol Biol Phys 15(5):1153–1159CrossRefPubMed
22.
Kruger S, Abd Elmageed ZY, Hawke DH, Worner PM, Jansen DA, Abdel-Mageed AB, Alt EU, Izadpanah R (2014) Molecular characterization of exosome-like vesicles from breast cancer cells. BMC Cancer 14:44CrossRefPubMedPubMedCentral
23.
Shelke GV, Lasser C, Gho YS, Lotvall J (2014) Importance of exosome depletion protocols to eliminate functional and RNA-containing extracellular vesicles from fetal bovine serum. J Extracell Vesicles 3:24783
24.
Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S, Pai SK, Liu W, Fukuda K, Chambers C et al (2011) Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med 208(13):2641–2655CrossRefPubMedPubMedCentral
25.
Aguirre-Ghiso JA, Estrada Y, Liu D, Ossowski L (2003) ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res 63(7):1684–1695PubMed
26.
Chery L, Lam HM, Coleman I, Lakely B, Coleman R, Larson S, Aguirre-Ghiso JA, Xia J, Gulati R, Nelson PS et al (2014) Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways. Oncotarget 5(20):9939–9951CrossRefPubMedPubMedCentral
27.
Sosa MS, Avivar-Valderas A, Bragado P, Wen HC, Aguirre-Ghiso JA (2011) ERK1/2 and p38α/β signaling in tumor cell quiescence: opportunities to control dormant residual disease. Clin Cancer Res 17(18):5850–5857CrossRefPubMedPubMedCentral
28.
Paciotti GF, Tamarkin L (1988) Interleukin-1 directly regulates hormone-dependent human breast cancer cell proliferation in vitro. Mol Endocrinol 2(5):459–464CrossRefPubMed
29.
Cowland JB, Muta T, Borregaard N (2006) IL-1beta-specific up-regulation of neutrophil gelatinase-associated lipocalin is controlled by IkappaB-zeta. J Immunol 176(9):5559–5566CrossRefPubMed
30.
Harris SA, Enger RJ, Riggs BL, Spelsberg TC (1995) Development and characterization of a conditionally immortalized human fetal osteoblastic cell line. J Bone Miner Res 10(2):178–186CrossRefPubMed
31.
Stoica A, Saceda M, Doraiswamy VL, Coleman C, Martin MB (2000) Regulation of estrogen receptor-α gene expression by epidermal growth factor. J Endocrinol 165(2):371–378CrossRefPubMed
32.
Stoica A, Saceda M, Fakhro A, Joyner M, Martin MB (2000) Role of insulin-like growth factor-I in regulating estrogen receptor-α gene expression. J Cell Biochem 76(4):605–614CrossRefPubMed
33.
West NR, Murphy LC, Watson PH (2012) Oncostatin M suppresses oestrogen receptor-α expression and is associated with poor outcome in human breast cancer. Endocr Relat Cancer 19(2):181–195CrossRefPubMed
34.
Chang HL, Sugimoto Y, Liu S, Ye W, Wang LS, Huang YW, Lin YC (2006) Keratinocyte growth factor (KGF) induces tamoxifen (Tam) resistance in human breast cancer MCF-7 cells. Anticancer Res 26(3A):1773–1784PubMed
35.
Petrel TA, Brueggemeier RW (2003) Increased proteasome-dependent degradation of estrogen receptor-α by TGF-β1 in breast cancer cell lines. J Cell Biochem 88(1):181–190CrossRefPubMedPubMedCentral
36.
Takahashi M, Otsuka F, Miyoshi T, Otani H, Goto J, Yamashita M, Ogura T, Makino H, Doihara H (2008) Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation. J Endocrinol 199(3):445–455CrossRefPubMed
37.
Danforth DN Jr, Sgagias MK (1991) Interleukin 1α blocks estradiol-stimulated growth and down-regulates the estrogen receptor in MCF-7 breast cancer cells in vitro. Cancer Res 51(5):1488–1493PubMed
38.
Danforth DN Jr, Sgagias MK (1993) Interleukin-1α and interleukin-6 act additively to inhibit growth of MCF-7 breast cancer cells in vitro. Cancer Res 53(7):1538–1545PubMed
39.
Lang JD, Berry SM, Powers GL, Beebe DJ, Alarid ET (2013) Hormonally responsive breast cancer cells in a microfluidic co-culture model as a sensor of microenvironmental activity. Integr Biol 5(5):807–816CrossRef
40.
Keshamouni VG, Mattingly RR, Reddy KB (2002) Mechanism of 17-β-estradiol-induced Erk1/2 activation in breast cancer cells. A role for HER2 AND PKC-delta. J Biol Chem 277(25):22558–22565CrossRefPubMed
41.
Svensson S, Jirstrom K, Ryden L, Roos G, Emdin S, Ostrowski MC, Landberg G (2005) ERK phosphorylation is linked to VEGFR2 expression and Ets-2 phosphorylation in breast cancer and is associated with tamoxifen treatment resistance and small tumours with good prognosis. Oncogene 24(27):4370–4379CrossRefPubMed
42.
Clark AS, West K, Streicher S, Dennis PA (2002) Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 1(9):707–717PubMed
43.
Wang H, Yu C, Gao X, Welte T, Muscarella AM, Tian L, Zhao H, Zhao Z, Du S, Tao J et al (2015) The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells. Cancer Cell 27(2):193–210CrossRefPubMedPubMedCentral
44.
Pinto MP, Badtke MM, Dudevoir ML, Harrell JC, Jacobsen BM, Horwitz KB (2010) Vascular endothelial growth factor secreted by activated stroma enhances angiogenesis and hormone-independent growth of estrogen receptor-positive breast cancer. Cancer Res 70(7):2655–2664CrossRefPubMedPubMedCentral
45.
Rhodes LV, Muir SE, Elliott S, Guillot LM, Antoon JW, Penfornis P, Tilghman SL, Salvo VA, Fonseca JP, Lacey MR et al (2010) Adult human mesenchymal stem cells enhance breast tumorigenesis and promote hormone independence. Breast Cancer Res Treat 121(2):293–300CrossRefPubMed
46.
Fuchs-Young R, Shirley SH, Lambertz I, Colby JK, Tian J, Johnston D, Gimenez-Conti IB, Donehower LA, Conti CJ, Hursting SD (2011) P53 genotype as a determinant of ER expression and tamoxifen response in the MMTV-Wnt-1 model of mammary carcinogenesis. Breast Cancer Res Treat 130(2):399–408CrossRefPubMed
47.
Sgagias MK, Kasid A, Danforth DN Jr (1991) Interleukin-1α and tumor necrosis factor-α (TNFα) inhibit growth and induce TNF messenger RNA in MCF-7 human breast cancer cells. Mol Endocrinol 5(11):1740–1747CrossRefPubMed
48.
Sosnoski DM, Norgard RJ, Grove CD, Foster SJ, Mastro AM (2015) Dormancy and growth of metastatic breast cancer cells in a bone-like microenvironment. Clin Exp Metastasis 32(4):335–344CrossRefPubMed
49.
Shiozawa Y, Pedersen EA, Havens AM, Jung Y, Mishra A, Joseph J, Kim JK, Patel LR, Ying C, Ziegler AM et al (2011) Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Investig 121(4):1298–1312CrossRefPubMedPubMedCentral
50.
Chen Z, Orlowski RZ, Wang M, Kwak L, McCarty N (2014) Osteoblastic niche supports the growth of quiescent multiple myeloma cells. Blood 123(14):2204–2208CrossRefPubMedPubMedCentral
51.
Lawson MA, McDonald MM, Kovacic N, Hua Khoo W, Terry RL, Down J, Kaplan W, Paton-Hough J, Fellows C, Pettitt JA et al (2015) Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche. Nat Commun 6:8983CrossRefPubMedPubMedCentral
52.
Pantschenko AG, Pushkar I, Anderson KH, Wang Y, Miller LJ, Kurtzman SH, Barrows G, Kreutzer DL (2003) The interleukin-1 family of cytokines and receptors in human breast cancer: implications for tumor progression. Int J Oncol 23(2):269–284PubMed
53.
Kumar S, Kishimoto H, Chua HL, Badve S, Miller KD, Bigsby RM, Nakshatri H (2003) Interleukin-1α promotes tumor growth and cachexia in MCF-7 xenograft model of breast cancer. Am J Pathol 163(6):2531–2541CrossRefPubMedPubMedCentral
54.
Voronov E, Shouval DS, Krelin Y, Cagnano E, Benharroch D, Iwakura Y, Dinarello CA, Apte RN (2003) IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci USA 100(5):2645–2650CrossRefPubMedPubMedCentral
55.
Saito M, Fan D, Lachman LB (1995) Antitumor effects of liposomal IL1α and TNFα against the pulmonary metastases of the B16F10 murine melanoma in syngeneic mice. Clin Exp Metastasis 13(4):249–259CrossRefPubMed
56.
Pezzella KM, Neville ME, Huang JJ (1990) In vivo inhibition of tumor growth of B16 melanoma by recombinant interleukin 1β. I. Tumor inhibition parallels lymphocyte-activating factor activity of interleukin 1β proteins. Cytokine 2(5):357–362CrossRefPubMed
57.
Nakamura S, Nakata K, Kashimoto S, Yoshida H, Yamada M (1986) Antitumor effect of recombinant human interleukin 1α against murine syngeneic tumors. Jpn J Cancer Res 77(8):767–773PubMed
58.
Gao H, Chakraborty G, Lee-Lim AP, Mo Q, Decker M, Vonica A, Shen R, Brogi E, Brivanlou AH, Giancotti FG (2012) The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 150(4):764–779CrossRefPubMedPubMedCentral
59.
60.
Bodo M, Baroni T, Tabilio A (2009) Haematopoietic and stromal stem cell regulation by extracellular matrix components and growth factors. J Stem Cells 4(1):57–69PubMed
61.
Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, Szallasi Z (2010) An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1809 patients. Breast Cancer Res Treat 123(3):725–731CrossRefPubMed
62.
Fernandez-Garcia B, Eiro N, Miranda MA, Cid S, Gonzalez LO, Dominguez F, Vizoso FJ (2016) Prognostic significance of inflammatory factors expression by stroma from breast carcinomas. Carcinogenesis 37(8):768–776CrossRefPubMed
63.
Mittempergher L, Saghatchian M, Wolf DM, Michiels S, Canisius S, Dessen P, Delaloge S, Lazar V, Benz SC, Tursz T et al (2013) A gene signature for late distant metastasis in breast cancer identifies a potential mechanism of late recurrences. Mol Oncol 7(5):987–999CrossRefPubMed
64.
Zhang XH, Jin X, Malladi S, Zou Y, Wen YH, Brogi E, Smid M, Foekens JA, Massague J (2013) Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell 154(5):1060–1073CrossRefPubMedPubMedCentral
65.
Lewis AM, Varghese S, Xu H, Alexander HR (2006) Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment. J Transl Med 4:48CrossRefPubMedPubMedCentral
66.
67.
Triozzi PL, Aldrich W (2010) Effects of interleukin-1 receptor antagonist and chemotherapy on host-tumor interactions in established melanoma. Anticancer Res 30(2):345–354PubMed
Metadata
Title
Downregulation of estrogen receptor and modulation of growth of breast cancer cell lines mediated by paracrine stromal cell signals
Authors
J. Huang
P. Woods
D. Normolle
J. P. Goff
P. V. Benos
C. J. Stehle
R. A. Steinman
Publication date
01-01-2017
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 2/2017
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-016-4052-0

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