**8. References**


actual EMT transition does take place as the initial population of cells is relatively homogeneous with respect to being epithelial in nature. Most if not all of the cells in culture can simultaneously undergo EMT whereas it is very likely that only a very small fraction of cells in a tumour acquire all of the characteristics enabling them to undergo a full transition, which may be why such mesenchymal-like cells have not been routinely reported by

The persistent problem of drug resistance and in particular the therapeutic failure of endocrine agents presents serious therapeutic issues especially in view of the success of this type of intervention in a significantly large proportion of women with breast cancer. Many studies have focused on elucidating the mechanisms responsible for *de novo* and *acquired* independence from estrogen. Consensus of opinion favours the view that signaling pathways mediated through a variety of peptide growth factors is largely responsible for the aggressive proliferation of tumours that have ceased to depend upon the ER, although no single unifying or even major factor has been identified. Somewhat in parallel, the last few years have witnessed an increasing number of reports describing the relatively recently recognized phenomenon of EMT, highlighting its similarity to the events leading to tumour invasion and vascular dissemination. Many of the key mediators of EMT particularly the transcriptional repression of E-cadherin by SNAIL appear to be critical steps in tumour progression. The association of mesenchymal-like features such as cadherin switching, loss of adhesion proteins and CD24, increased vimentin and fibronectin, with ER-ve tumours, have been sporadically, almost anecdotally reported in the literature over the last decade or more. We have now found evidence to show that the acquisition of endocrine independence, due to induced ER loss, by previously ER+ breast cancer cells, is accompanied by all the hallmark features of EMT. Although it is still far from clear whether the two processes are occurring side by side or whether either is causal of the other, it seems reasonable to conclude that loss of ER can directly trigger EMT. It remains to be seen whether restoration of ER in the trans-differentiated cells can reverse EMT and allow the

We thank Kuwait University Research Administration for financial support in the form of

Aguilera O, Fraga MF, Ballestar E, Paz MF, Herranz M, et al: Epigenetic inactivation of the

Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R & Kasimir-Bauer S: Stem cell and epithelial-

Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene

mesenchymal transition markers are frequently over-expressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 11:R46, 2009. Al Saleh S, Sharaf LH & Luqmani YA: Signalling pathways involved in endocrine resistance

in breast cancer and associations with epithelial to mesenchymal transition. Int J

pathologists (Thompson et al., 2008).

cells to regain estrogen dependence.

25: 4116–4121, 2006.

Oncol 38(5):1197-217, 2011.

**7. Acknowledgements** 

Grant YM08/09.

**8. References** 

**6. Summary** 


Endocrine Resistance and Epithelial Mesenchymal Transition in Breast Cancer 475

Creighton CJ, Fu X, Hennessy BT, et al: Proteomic and transcriptomic profiling reveals a link

Dandachi N, Hauser-Kronberger C, More E, et al: Co-expression of tenascin-C and vimentin

Das S, Becker B, Hoffmann FM & Mertz JE: Complete reversal of epithelial to mesenchymal

Dhasarathy A, Kajita M & Wade PA: The transcription factor snail mediates epithelial to

DiMeo TA, Anderson K, Phadke P, et al: A novel lung metastasis signature links wnt

Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS, et al: Role

Dorssers LC, van Agthoven T, Dekker A, van Agthoven TL & Kok EM: Induction of

Emmen JM, Couse JF, Elmore SA, Yates MM, Kissling GE & Korach KS: In vitro growth and

Faridi J, Wang L, Endemann G & Roth RA: Expression of constitutively active Akt-3 in

Fillmore CM & Kuperwasser C: Human breast cancer cell lines contain stem like cells that

Fillmore CM & Kuperwasser C: Human breast cancer cell lines contain stem-like cells that

Fisher B, Dignam J, Wolmark N, Wickerham, DL, Fisher ER, et al: Tamoxifen in treatment of

Font de Mora J & Brown M: AIB1 is a conduit for kinase-mediated growth factor signaling

Forster C, Makela S, Warri A, Kietz S, Becker D, Hultenby K, Warner M & Gustafsson JA:

Frasor J, Danes JM, Komm B, Chang KC, Lyttle CR & Katzenellenbogen BS: Profiling of

proliferation and cell phenotype. Endocrinology 144: 4562–4574, 2003.

ER+ breast cancer. Breast Cancer Res 12(3):R40, 2010.

receptors, and onco-proteins. J Pathol 193: 181-189, 2001.

basal-like breast cancer. Cancer Res 69: 5364-5373, 2009.

cells. Breast Cancer Res 6: R605-R615, 2004.

integration site. Mol. Endocrinol 7: 870–878, 1993.

cells in vivo. Clin Cancer Res 9: 2933–2939, 2003.

chemotherapy. Breast Cancer Res 10: R25, 2008.

randomised controlled trial. Lancet 12; 353(9169):1993-2000.

to the estrogen receptor. Mol Cell Biol 20: 5041-5047, 2000.

gland epithelium. Proc Natl Acad Sci USA 99:15578-15583, 2002.

Breast cancer res 10(2) : R25, 2008.

Cell Biol 10: 94-112, 2009.

21: 2907 2918, 2007.

2817-2826, 2005.

between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in

in human breast cancer cells indicates phenotypic transdifferentiation during tumour progression: correlation with histopathological parameters, hormone

transition requires inhibition of both ZEB expression and the Rho pathway. BMC

mesenchymal transitions by repression of estrogen receptor-alpha. Mol Endocrinol

signalling with cancer cell self-renewal and epithelial-mesenchymal transition in

of Notch signaling in cell-fate determination of human mammary stem/progenitor

antiestrogen resistance in human breast cancer cells by random insertional mutagenesis using defective retroviruses: identification of bcar-1, a common

ovulation of follicles from ovaries of estrogen receptor (ER){alpha} and ER{beta} null mice indicate a role for ER{beta} in follicular maturation. Endocrinology 146:

MCF-7 breast cancer cells reverses the estrogen and tamoxifen responsivity of these

self-renew, give rise to phenotypically diverse progeny & survive chemotherapy.

self-renew, give rise to pheno-typically diverse progeny and survive

intraductal breast cancer. National Surgical Adjuvant Breast and Bowel Project B-24

Involvement of estrogen receptor beta in terminal differentiation of mammary

estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of


Bunone G, Briand PA, Miksicek RJ & Picard D: Activation of the unliganded estrogen

Cai D, Iyer A, Felekkis KN, Near RI, Luo Z, et al: AND-34/BCAR3, a GDP exchange factor

Caldon CE, Sergio CM, Schütte J, Boersma MN, Sutherland RL, et al: Estrogen regulation of cyclin E2 requires cyclin D1, but not c-Myc. Mol Cell Biol 29:4623–4639, 2009. Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S and Nakshatri H:

new model for anti-estrogen resistance. J Biol Chem 276: 9817-9824, 2001 Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, et al: The transcription factor

Cappelletti V, Celio L, Bajetta E, Allevi A, Longarini R, et al: Prospective evaluation of

Care A, Silvani A, Meccia E, Mattia G, Peschle C & Colombo MP: Transduction of the SkBr3

Carrio M, Arderiu G, Myers C & Boudreau NJ: Homeobox D10 induces phenotypic

Chaffer CL, Thompson EW & Williams ED. Mesenchymal to epithelial transition in

Chan CM, Martin LA, Johnston SR, Ali S & Dowsett M: Molecular changes associated with

Chen H, Chung S & Sukumar S: HOXA5-induced apoptosis in breast cancer cells is

Chen JD &Evans RM: A transcriptional co-repressor that inter-acts with nuclear hormone

Cheng GZ, Chan J, Wang Q, Zhang W, Sun CD & Wang LH: Twist transcriptionally up-

Chu IM, Hengst L & Slingerland JM: The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nature Rev Cancer 8: 253–267, 2008. Come C, Magnino F, Bibeau F, *et al*: SNAIL and SNAIL2 play distinct roles during breast

term estrogen deprivation. J Steroid Biochem Mol Biol 81: 333–341, 2002. Charafe-Jauffret E, Ginestier C, Monville F, Finetti P, Adélaïde J, et al: Gene expression

development and disease. Cells Tissues Organs 185: 7–19, 2007.

mediated by caspases 2 and 8. Mol Cell Biol 24: 924-935, 2004.

resistance to paclitaxel. Cancer Res 67(5): 1979–1987, 2007.

carcinoma progression. Clin Cancer Res 12: 5395-5402, 2006. Coqueret O: Linking cyclins to transcriptional control. Gene 299: 35–55, 2002.

in elderly breast cancer patients. Endocr-Relat Cancer 11:761–770, 2004. Care A, Felicetti F, Meccia E, et al: HOXB7: a key factor for tumor-associated angiogenic

the cyclin D1 promoter. Cancer Res 63: 6802-6808, 2003.

EMBO J 15: 2174-2183, 1996.

expression. Nat Cell Biol 2: 76-83, 2000.

switch. Cancer Res 61: 6532-6539, 2001.

1998.

7177-7185, 2005.

Oncogene 25(15):2273-84, 2006.

receptors. Nature 377: 454-457, 1995.

receptor by EGF involves the MAP kinase pathway and direct phosphorylation.

whose over-expression confers antiestrogen resistance, activates Rac, PAK1, and

Phosphatidylinositol 3-kinase/akt- mediated activation of estrogen receptor α: a

Snail controls epithelial-mesenchymal transitions by repressing E-cadherin

estrogen receptor-beta in predicting response to neoadjuvant antiestrogen therapy

breast carcinoma cell line with the HOXB7 gene induces bFGF expression, increases cell proliferation and reduces growth factor dependence. Oncogene 16: 3285-3289,

reversion of breast tumor cells in a three-dimensional culture model. Cancer Res 65:

the acquisition of estrogen hypersensitivity in MCF-7 breast cancer cells on long-

profiling of breast cell lines identifies potential new basal markers.

regulates AKT2 in breast cancer cells leading to increased migration, invasion, and


Endocrine Resistance and Epithelial Mesenchymal Transition in Breast Cancer 477

Hazan RB, Phillips GR, Qiao RF, Norton L & Aaronson SA: Exogenous expression of N-

Hazan RB, Qiao R, Keren R, Badano I, & Suyama K: Cadherin switch in tumour progression.

Hebbard L, Steffen A, Zawadzki V, Fieber C, Howells N, et al: CD44 expression and

Hennessy BT, et al: Characterization of a naturally occurring breast cancer subset enriched

Herynk, MH & Fuqua SA: Estrogen receptor mutations in human disease. Endocr Rev 25:

Hiscox S, Borley A, Nicholson RI & Barett-Lee P: Epithelial-mesenchymal transition (EMT)

Hollier BG, Evans K & Mani SA: The epithelial-to-mesen-chymal transition and cancer stem

Honma N, Horii R, Iwase T, Saji S, Younes M, et al. Clinical importance of estrogen receptor-

Horlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, et al: Ligand-independent repression by

Hoskins JM, Carey LA & McLeod HL. CYP2D6 and tamoxifen: DNA matters in breast

Howell A, Pippen J, Elledge RM, Mauriac L, Vergote I, Jones SE, et al: Fulvestrant *vs*

Hua G, Zhu B, Rosa F, Deblon N, Adélaïde J, et al: A negative feedback regulatory loop

Huber MA, Kraut N & Beug H: Molecular requirements for epithelial–mesenchymal transi tion during tumor progression. Curr Opin Cell Biol 17: 548–558, 2005. Huber MA, Azoitei N, Baumann B, Grünert S, Sommer A, et al: NF-kappaB is essential for

Hui R, Finney GL, Carroll JS, Lee CS, Musgrove EA & Sutherland RL: Constitutive

antiestrogens in T-47D breast cancer cells. Cancer Res 62:6916–6923, 2002.

Cell Biol 148: 779-790, 2000.

113(14):2619-2630, 2000.

69:4116–4124, 2009.

869-898, 2004.

2009.

2005.

6923, 2002.

Ann NY Acad Sci 1014: 155-163, 2004.

Publishers, New York, pp81-95, 2007.

Clin Oncol 26: 3727–3734, 2008.

cancer. Nature Rev Cancer 9:576–586, 2009.

in breast cancer cells. Mol Cancer Res 7: 402–414, 2009.

377: 397-404, 1995.

cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J

regulation during mammary gland development and function, J Cell Sci

in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res

and its involvement in acquired endocrine resistance in breast cancer.Chapter 5. In: Cancer Drug Resistance Research perspectives. Torres LS (ed.) Nova Science

cells: a coalition against cancer therapies. J Mamm Gland Biol Neoplasia 14: 29-43,

β evaluation in breast cancer patients treated with adjuvant tamoxifen therapy. J

the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature

anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials. Cancer 104: 236–239,

associates the tyrosine kinase receptor ERBB2 and the transcription factor GATA4

epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest Hui R, Finney GL, Carroll JS, Lee CS, Musgrove EA & Sutherland RL.: Constitutive overexpression of cyclin D1 but not cyclin E confers acute resistance to antiestrogens in T-47D breast cancer cells. Cancer Res 62: 6916–

overexpression of cyclin D1 but not cyclin E confers acute resistance to


Fujita N, Jaye DL, Kajita M. Geigerman C, Moreno CS, et al: MTA3, a Mi-2/NuRD Complex

Fuqua SA, Wiltschke C, Zhang QZ, Borg A, Castles CG, et al: A hypersensitive estrogen

Fuxe J, Vincent T, & de Herreros AJ: Transcriptional crosstalk between TGFβ and stem cell

Gadalla SE, Alexandraki A, Lindström MS, Nistér, M & Ericsson C: Uncoupling of the ERα

Gebeshuber CA, Zatloukal K & Martinez J: miR-29a suppresses tristetraprolin, which is a regulator of epithelial polarity and metastasis, EMBO Rep 10(4):400-5, 2009. Gilles C, Polette M, Mestdagt M, et al: Transactivation of vimentin by beta-catenin in human

Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, et al: ALDH1 is a marker of

Gjerdrum C, Tiron C, Høiby T, Stefansson I, Haugen H, et al: Axl is an essential epithelial-

Green S, Walter P, Kumar V, Krust A, Bornert JM, Argos P & Chambon P: Human oestrogen

Greenberg G & Hay ED: Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J Cell Biol 95: 333-339, 1982. Gregory PA, Bracken CP, Bert AG & Goodall GJ: MicroRNAs as regulators of epithelial–

Gronemeyer H: Transcription activation by estrogen and proges-terone receptors. Ann Rev

Gururaj AE, Rayala SK, Vadlamudi RK & Kumar R: Novel mechanisms of resistance to

Gutierrez MC, Detre S, Johnston S, Mohsin SK, Shou J, *et al*: Molecular changes in tamoxifen-

Hafizi S & Dahlbäck B: Signaling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Cytok Growth Factor Rev 17: 295-304, 2006. Hall JM & McDonnell DP: The estrogen receptor beta-isoform (ERbeta) of the human

Hartwell KA, Muir B, Reinhardt F, et al: The Spemann organizer gene, Goosecoid, promotes

Hay ED. An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) 154:8–20,

mitogen-activated protein kinase. J Clin Oncol 23: 2469*-*2476, 2005.

tumor metastasis. Proc Natl Acad Sci USA 103: 18969-18974, 2006.

endocrine therapy: genomic and nongenomic considerations. Clin Cancer Res 12:

resistant breast cancer: relation-ship between estrogen receptor, HER-2, and p38

estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology 140: 5566–

patient survival. Proc Natl Acad Sci USA 107: 1124-1129, 2010.

mesenchymal transition. Cell Cycle 7: 3112–3118, 2008.

breast cancer cell lines. BBRC 405 (4): 581-587 , 2005.

breast cancer cells. Cancer Res 63: 2658-2664, 2003.

outcome. Cell Stem Cell 1: 555-567, 2007.

219, 2003.

Cycle 9 (12): 2363–2374, 2010.

320:134–139, 1986.

Genet 25: 89-123, 1991.

1001s–1007s, 2006.

5578, 1999.

1995.

2000.

Subunit, Regulates an Invasive Growth Pathway in Breast Cancer. Cell 113: 207–

receptor-alpha mutation in premalignant breast lesions. Cancer Res 60:4026–4029,

pathways in tumor cell invasion: role of EMT promoting Smad complexes. Cell

regulated morphological phenotype from the cancer stem cell phenotype in human

normal and malignant human mammary stem cells and a predictor of poor clinical

to-mesenchymal transition-induced regulator of breast cancer metastasis and

receptor cDNA: Sequence, expression and homology with v-erb. Nature (Lond.)


Endocrine Resistance and Epithelial Mesenchymal Transition in Breast Cancer 479

Lechner JF, Fugaro JM, Wong Y, Pass HI, Harris CC & Belinsky SA: Perspective: cell

Levin ER: Bidirectional signaling between the estrogen receptor and the epidermal growth

Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100: 672–679, 2008. Lim E, Wu D, Pal B, Bouras T, Asselin-Labat ML, et al: Transcriptome analyses of mouse

Linger RM, Keating AK, Earp HS & Graham DK: TAM receptor tyrosine kinases: biologic

Lopez-Tarruella S & Schiff R: The dynamics of estrogen receptor status in breast cancer:

Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS & Smithies O: Alteration of

Luqmani YA, Al Azmi A, Al Bader M, Abraham G & El Zawahri M: Modification of gene

Ma L, Teruya-Feldstein J & Weinberg RA: Tumour invasion and metastasis initiated by

Ma XJ, Wang Z, Ryan PD, et al: A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell 5: 607-616, 2004. Magnifico A, Albano L, Campaner S, Delia D, Castiglioni F, et al: Tumor-initiating cells of

Mandlekar S & Kong AN: Mechanisms of tamoxifen induced apoptosis. Apoptosis 6: 469–

Mani SA, Yang J, Brooks M, et al: Mesenchyme Forkhead 1 (FOXC2) plays a key role in

Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, et al: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133: 704-715, 2008. Martin LA, Farmer I, Johnston SR, Ali S, Marshall C & Dowsett M: Enhanced estrogen

Masamura S, Santner SJ, Heitjan DF & Santen RJ: Estrogen deprivation causes estradiol

Massarweh S & Schiff R: Unraveling the mechanisms of endocrine resistance in breast cancer: new therapeutic opportunities. Clin Cancer Res 13(7):1950-4, 2007.

reshaping the paradigm. Clin. Cancer Res. 13:6921–25, 2007.

microRNA-10b in breast cancer. Nature 449: 682–688, 2007.

Trastuzumab sensitive. Clin Cancer Res 15: 2010-2021, 2009.

Leo C & Chen JD: The srcfamily of nuclear receptor co- activators. Gene 245: 1-11, 2000. Lester RD, Jo M, Montel V, et al: uPAR induces epithelial mesenchymal transition in

hypoxic breast cancer cells. J Cell Biol 178: 425-436, 2007.

factor receptor. Mol Endocrinol 17: 309-317, 2003.

pathways. Breast Cancer Res 12:R21, 2010.

cancer cells. Int J Oncol 34: 231-242, 2009

Acad Sci USA 104: 10069-10074, 2007.

Chem. 278:30458–30468, 2003.

Radiat Res 155: 235-238, 2001

Cancer Res 100: 35-83, 2008

11166, 1993.

477, 2001.

2925, 1995.

differentiation theory may advance early detection of and therapy for lung cancer.

and human mammary cell subpopulations reveal multiple conserved genes and

functions, signalling, and potential therapeutic targeting in human cancer. Adv

reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci USA 90: 11162–

expression induced by siRNA targeting of estrogen receptor in MCF7 human breast

HER2-positive carcinoma cell lines express the highest oncoprotein levels and are

metastasis and is associated with aggressive basal-like breast cancers. Proc Natl

receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation, J. Biol.

hypersensitivity in human breast cancer cells. J Clin Endocrinol Metab 80:2918–


Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, et al: Regulation of

Hutcheson IR, Knowlden JM, Madden TA, Barrow D, Gee JM, et al.: Oestrogen receptor-

Iseri OD, Kars DM, Arpaci F, Atalay C, Pak I & Gunduz U: Drug resistant MCF-7 cells

Ishii Y, Waxman S & Germain D: Tamoxifen stimulates the growth of cyclin D1-

Joel PB, Smith J, Sturgill TW, Fisher TL, Blenis J & Lannigan DA: pp90rsk1 regulates

Johnston SR, Saccani-Jotti G, Smith IE, Salter J, Newby J, et al: Changes in estrogen receptor,

Johnston SR, Lu B, Scott GK, Kushner PJ, Smith IE, et al: Increased activator protein-1 DNA

Johnston SR & Dowsett M: Aromatase inhibitors for breast cancer: lessons from the

Kalluri R & Weinberg RA. The basics of epithelial–mesenchymal transition. J Clin Invest Jun

Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, et al: Activation of the estrogen

Kajiyama H, Hosono S, Terauchi M, Shibata K, Ino K, Yamamoto E, et al: Twist expression

Kouros-Mehr H, Kim JW, Bechis SK, & Werb Z: GATA-3 and the regulation of the

Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S & Gustafsson JA: Cloning of a novel

Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, et al: Comparison of the ligand

Kushner PJ, Agard DA, Greene GL, Scanlan TS, Shiau AK, et al: Estrogen receptor pathways

Laffin B, Wellberg E, Kwak HI, et al: Loss of singleminded-2s in the mouse mammary gland

Le Romancer M, Treilleux I, Leconte N, Robin-Lespinasse N, et al: Regulation of estrogen

mammary luminal cell fate. Curr Opin Cell Biol 20: 164–170, 2008.

to AP-1. J Steroid Biochem Mol Biol 74: 311-317, 2000.

and matrix metalloprotease 2. Mol Cell Biol 28: 1936-1946, 2008.

and activator of transcription. Cancer Res 68: 852–860, 2008.

acquired tamoxifen resistance. Clin Cancer Res 5: 251-256, 1999.

laboratory. Nature Reviews Cancer 3:821–831, 2003.

cells. Breast Cancer Res Treat 81: 81–93, 2003.

Pharmacother: 65(1):40-45, 2011.

Cell Biol 18: 1978-1984, 1998.

119(6): 1420–8, 2009.

Oncology 71:394–401, 2006.

Endocrinology 138: 863–870, 1997.

1491-1494, 1995.

5930, 1996.

2008.

cancer, Cancer Res 55: 3331–3338, 1995.

663–666, 2008.

ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen. Nature 456:

mediated modulation of the EGFR/MAPK pathway in tamoxifenresistant MCF-7

exhibit epithelial-mesenchymal transition gene expression pattern. Biomed

overexpressing breast cancer cells by promoting the activation of signal transducer

estrogen receptor mediated transcription through phosphorylation of Ser-167. Mol

progesterone receptor, and pS2 expression in tamoxifen resistant human breast

binding and c-jun NH2-terminal kinase activity in human breast tumors with

receptor through phosphorylation by mitogenactivated protein kinase. Science 270:

predicts poor clinical outcome of patients with clear cell carcinoma of the ovary.

receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93: 5925–

binding specificity and transcript tissue distribution of estrogen receptors α and β.

induces an epithelial-mesenchymal transition associated with up-regulation of slug

rapid signaling through arginine methylation by PRMT1. Mol Cell 31: 212–221,


Endocrine Resistance and Epithelial Mesenchymal Transition in Breast Cancer 481

Osborne CK, Schiff R, Fuqua SA & Shou J: Estrogen receptor: current understanding of its activation and modulation. Clin. Cancer Res: 7 (Suppl 12): S4338–S4342, 2001. Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, et al : Double-blind, randomized trial

therapy: results of a North American trial. Int J Oncol 20: 3386–3395, 2002. Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, et al: Role of the estrogen

Osborne CK & Schiff R: Estrogen-receptor biology: continuing progress and therapeutic

Osborne CK & Schiff R: Mechanisms of endocrine resistance in breast cancer. Ann Rev Med.

Ottaviano YL, Issa JP, Parl FF, Smith HS, Baylin SB & Davidson NE: Methylation of the

Otto C, Rohde-Schulz B, Schwarz G, Fuchs I, Klewer M, et al: G Protein-Coupled Receptor

Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y & Wrana JL: Regulation of the

Parker KK, Lepre Brock A, Brangwynne C, Mannix RJ et al : Directional control of

Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, et al: Differential Ligand activation of estrogen receptors ERalpha and ERbeta at AP-1 sites. Science 277:1508–1510, 1997. Pantel K, Brakenhoff RH & Brandt B: Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer 8:329-340, 2008. Parikh P, Palazzo JP, Rose LJ, Daskalakis C, & Weigel RJ: J Am Coll Surg 200: 705–710, 2005. Park SM, Gaur AB, Lengyel E & Peter ME: The miR-200 family determines the epithelial

Parl FF: Multiple mechanisms of estrogen receptor gene repression contribute to ER-

Peinado H, Olmeda D & Cano A: Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nature Rev Cancer 7: 415–428, 2007. Perez-Losada J, Sanchez-Martin M, Rodriguez-Garcia A, Sanchez M, Orfao A, et al.

Pérez-Tenorio G, Berglund F, Esguerra Merca A, Nordenskjöld B, Rutqvist LE, et al:

Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, et al: Molecular portraits of human

Pettersson K, Delaunay F & Gustafsson JA: Estrogen receptor β acts as a dominant regulator

negative breast cancer. Pharmacogenomics J 3:251–253, 2003.

factor c-kit signaling pathway. Blood 100: 1274–1286, 2002.

tamoxifen in breast cancer. Int J Oncol 28: 1031–1042, 2006.

of estrogen signalling. Oncogene 19: 4970–4978, 2000

breast tumours. Nature 406:747–752, 2000.

cancer. J Natl Cancer Inst 95, 353–361, 2003.

implications. J Clin Oncol 23:1616–1622, 2005.

Endocrinology 149 (10): 4846-4856, 2008.

forces. FASEB J 16: 1195-1204, 2002.

Genes Dev 22: 894–907, 2008.

human breast cancer cells. Cancer Res 54: 2552–2555, 1994.

62:233-47, 2011.

307: 1603-1609, 2005.

comparing the efcacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine

receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast

estrogen receptor gene CpG island marks loss of estrogen receptor expression in

30 Localizes to the Endoplasmic Reticulum and Is Not Activated by Estradiol.

polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science

lamellipodia extension by constraining cell shape and orienting cell tractional

phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2.

Zinc-finger transcription factor Slug contributes to the function of the stem cell

Cytoplasmic p21WAF1/CIP1 correlates with Akt activation and poor response to


Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, et al: Tamoxifen resistance in

McClelland RA, Barrow D, Madden TA, Dutkowski CM, Pamment J, et al: Enhanced

McKenna NJ, Lanz Rb & O'Malley BW: Nuclear receptor co-regulators: cellular and

Mehra R, Varambally S, Ding L, Shen R, Sabel MS, et al: Identification of GATA3 as a breast

Miller GJ, Miller HL, van Bokhoven A, et al: Aberrant HOXC expression accompanies the malignant phenotype in human prostate. Cancer Res 63: 5879-5888, 2003. Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, et al: The transcriptional repressor Snail promotes mammary tumour recurrence. Cancer Cell 8: 197-209, 2005. Morel AP, Lievre M, Thomas C, et al: Generation of breast cancer stem cells through

Moreno-Bueno G, Portillo F & Cano A: Transcriptional regulation of cell polarity in EMT

Moustakas A & Heldin CH: Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci 98:1512–1520, 2007. Moustakas A & Heldin CH: The regulation of TGFβ signal transduction. Development 136:

Murphy LC & Watson PH: Is oestrogen receptor-β a predictor of endocrine therapy responsiveness in human breast cancer? Endocr Relat Cancer 13: 327–334, 2006. Musgrove EA & Sutherland RL: Biological determinants of endocrine resistance in breast

Naora H, Yang YQ, Montz FJ, Seidman JD, Kurman RJ & Roden Rb: A serologically

Nicholson RI, Staka C, Boyns F, Hutcheson IR & Gee JM: Growth factor-driven mechanisms

Normanno N, Qi CF, Gullick WJ, Persico G, Yarden Y, et al: Expression of amphiregulin,

Normanno N, Di Maio M, De Maio E, De Luca A, De Matteis A, et al: Mechanisms of

Onder TT, Gupta PB, Mani SA, Yang J, Lander ES & Weinberg RA: Loss of E-cadherin

Orlichenko LS & Radisky DC: Matrix metalloproteinases stimulate epithelial-mesenchymal transition during tumour development. Clin Exp Metastasis 25: 593-600, 2008.

identified tumor antigen encoded by a homeobox gene promotes growth of ovarian

associated with resistance to estrogen deprivation in breast cancer: new

cripto-1 and heregulin-a in human breast cancer cell lines. Int J Oncol 2: 903-911,

endocrine resistance and novel therapeutic strategies in breast cancer. Endocr Relat

promotes metastasis via multiple downstream transcriptional pathways. Cancer

epithelial-mesenchymal transition. PLoS One 3: e2888, 2008.

epithelial cells. Proc Natl Acad Sci USA 98: 4060-4065, 2001.

opportunities for therapy. Endocr Relat Cancer 11: 623-641, 2004.

progression. Breast Cancer Res 13(1):202-211, 2011.

molecular biology. Endocr Rev 20: 321-344, 1999.

and cancer. Oncogene 27: 6958–6969, 2008.

cancer. Nat Rev 9: 631-643, 2009.

Cancer 12: 721-747, 2005.

Res 68: 3645-3653, 2008.

Endocrinology 142: 2776–2788, 2001.

11259–11264, 2005.

3699 -3714, 2009.

1993.

breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer research 68(3):826-33, 2008. May CD, Sphyris N, Evans KW, Werden SJ, Guo W, & Mani SA: Epithelial mesenchymal

transition and cancer stem cells: a dangerously dynamic duo in breast cancer

epidermal growth factor receptor signaling in MCF7 breast cancer cells after longterm culture in the presence of the pure antiestrogen ICI 182,780 (Faslodex).

cancer prognostic marker by global gene expression meta-analysis. Cancer Res 65:


Endocrine Resistance and Epithelial Mesenchymal Transition in Breast Cancer 483

Roger P, Sahla ME, Mäkelä S, Gustafsson JA, Baldet P & Rochefort H: Decreased expression

Rosner W, Hryb DJ, Khan MS, Nakhla AM & Romas NA: Androgen and estrogen signaling

Rountree MR, Bachman KE & Baylin SB: DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nature Genet 25:269–277, 2000. Saeki T, Cristiano A, Lynch MJ, Brattain M, Kim N, et al: Regulation by estrogen through the

Sabbah M, Emami S, Redeuilh G, Julien S, Prévost G, et al. (2008) Molecular signature and

Safe S: Transcriptional activation of genes by 17 betaestradiol through estrogen receptor-Sp1

Salloum A (2010). Responsiveness to growth stimulators of MCF7 breast cancer cells

Salomon DS, Brandt R, Ciardiello F & Normanno N: Epidermal growth factor-related

Sánchez-Martín M, Rodríguez-García A, Pérez-Losada J, Sagrera A, Read AP, et al: SLUG

Santen RJ, Song RX, Zhang Z, Kumar R, Jeng MH, et al: Adaptive hypersensitivity to

Santisteban M, Reiman JM, Asiedu MK, et al: Immune-induced epithelial to mesenchymal

Sarrio D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G &Palacios J:

Shaw JA, Udokang K, Mosquera JM, Chauhan H, Jones JL & Walker RA: Oestrogen

Sheridan C, Kishimoto H, Fuchs RK, Mehrotra S, Bhat-Nakshatri P, et al: CD44+, CD24–

Shi L, Dong B, Li Z, Lu Y, Ouyang T, Li J, Wang T, et al. Expression of ER-α36, a novel

Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, et al: Molecular definition of breast tumor heterogeneity. Cancer Cell 11: 259-273, 2007. Song RX, Santen RJ, Kumar R, Adam L, Jeng MH, Masamura S & Yue W: Adaptive

Cancer Res 61:2537–2541, 2001.

cancers. Drug Resistance Updates 11: 123–151.

interactions. Vitam Horm 62: 231-252, 2001.

64: 100–106, 1999.

1955-1963, 1991.

University.

232, 1995.

3231–3236, 2002.

Cancer 10:111–130, 2003.

Pathol. 198: 450–457, 2002.

phenotype. Cancer Res 68: 989-997, 2008.

metastasis. Breast Cancer Res 8: R59, 2006.

cancer. J Clin Oncol 27:3423–3429, 2009.

Molecular and Cell Endocrinol 193:29–42, 2002a.

of estrogen receptor beta protein in proliferative preinvasive mammary tumors.

at the cell membrane via G-proteins and cyclic adenosine monophosphate. *Steroids*

50-flanking region of the transforming growth factor alpha gene. Mol Endocrinol 5:

therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial

transfected with estrogen receptor siRNA constructs. MSc Thesis Kuwait

peptides and their receptors in human malignancies. Crit Rev Oncol Hemat 19: 183-

(SNAI2) deletions in patients with Waardenburg disease. Hum. Mol. Genet 11:

estrogen: mechanism for superiority of aromatase inhibitors over selective estrogen receptor modulators for breast cancer treatment and prevention. Endocr Relat

transition in vivo generates breast cancer stem cells. Cancer Res 69: 2887-2895, 2009.

Epithelial-mesenchymal transition in breast cancer relates to the basal-like

receptors alpha and beta differ in normal human breast and breast carcinomas, J.

breast cancer cells exhibit enhanced invasive properties: an early step necessary for

variant of estrogen receptor α, and resistance to tamoxifen treatment in breast

mechanisms induced by long-term estrogen deprivation in breast cancer cells.


Pieper FR, Van de Klundert FA, Raats JM, et al: Regulation of vimentin expression in

Pluijm G. Epithelial plasticity, cancer stem cells and bone metastasis formation. Bone 48: 37-

Polette M, Mestdagt M, Bindels S, et al: Beta-catenin and ZO-1: shuttle molecules involved

Polyak K & Weinberg RA: Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9: 265-273, 2009. Prall OWJ, Rogan EM, Musgrove EA, Watts CKW & Sutherland RL: c-Myc or cyclin D1

Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI , et al: Phenotypic and

Raman V, Martensen SA, Reisman D, et al: Compromised HOXA5 function can limit p53

Raouf A, Zhao Y, To K, Stingl J, Delaney A, Barbara M, Iscove N, et al: Transcriptome

Ray P, Ghosh SK, Zhang DH & Ray A: Repression of inter-leukin-6 gene expression by17

Razandi M, Pedram A, Park ST & Levin ER: Proximal events in signaling by plasma

Riggins RB, Quilliam LA & Bouton AH: Synergistic promotion of c-Src activation and cell migration by Cas and AND-34/BCAR3. J Biol Chem 278: 28264–28273, 2003. Riggins RB, Zwart A, Nehra R & Clarke R: The nuclear factor κB inhibitor parthenolide

Riggins RB, Schrecengost RS & Guerrero MS and Bouton AH: Pathways to tamoxifen

Riggins RB, Lan PJ, Klimach U, Zwart A, Cavalli RL et al: ERRγ mediates tamoxifen

Ring A & Dowsett M: Mechanisms of tamoxifen resistance. Endocr Relat Cancer 11: 643–658,

Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL & Wolffe AP: DNMT1 forms a

Robertson JF, Osborne CK, Howell A, Jones SE, Mauriac L, et al: Fulvestrant vs anastrozole

survival analysis of two multicenter trials. Cancer 104: 236-239, 2005. Robson EJ, Khaled WT, Abell K & Watson CJ: Epithelial-to-mesenchymal transition confers

expression in human breast tumours. Nature 405: 974-978, 2000.

membrane estrogen receptors. J Biol Chem 278: 2701-2712, 2003.

resistant breast cancer cells. Mol. Cancer Ther 4: 33–41, 2005.

responsive promoters. Nature Genet 25:338–342, 2000.

tamoxifen sensitivity. Cancer Res 66: 5985–5988, 2006.

in tumor invasion-associated epithelial-mesenchymal transition processes. Cells

mimics estrogen effects on cyclin E-Cdk2 activation and cell cycle reentry. Mol Cell

molecular characterization of the claudin-low intrinsic subtype of breast cancer.

analysis of the normal human mammary cell commitment and differentiation

beta-estradiol: inhibition of the DNA-binding activity of the transcription factors NF-IL6 and NF-kappa B by the estrogen receptor. FEBS Lett 409: 79-85, 1997. Rayala SK, Molli PR & Kumar R: Nuclear p21- activated kinase 1 in breast cancer packs off

restores ICI 182,780 (Faslodex; fulvestrant)-induced apoptosis in antiestrogen-

resistance in novel models of invasive lobular breast cancer. Cancer Res. 68:8908–

complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-

for the treatment of advanced breast carcinoma: a prospectively planned combined

resistance to apoptosis in three murine mammary epithelial cell lines.

cultured epithelial cells. Eur J Biochem 210: 509-519, 1992

43, 2011

Tiss Organs 185: 61-65, 2007.

Biol 18: 4499–4508, 1998.

B*reast Cancer Res* 12:R68, 2010.

process. Cell Stem Cell 3: 109-118, 2008.

resistance. Cancer Lett 256: 1-24, 2007.

Differentiation 74: 254-264, 2006.

8917, 2008.

2004.


Endocrine Resistance and Epithelial Mesenchymal Transition in Breast Cancer 485

van Agthoven T, van Agthoven TL, Dekker A, van der Spek PJ, Vreede L, et al:

Vincan E & Barker N: The upstream components of the Wnt signalling pathway in the

Waerner T, Alacakaptan M, Tamir I, Oberauer R, Gal A, et al: a cytokine essential for EMT,

Wang Y, Dean JL, Millar EKA, Tran TH, McNeil CH, et al: Cyclin D1b is aberrantly

Wang Z, Bannerji S, Li Y, Rahman KMW, Zhang Y & Sarkar FH: Down-regulation of notch-1

Watson MA, Ylagan LR, Trinkaus KM, Gillanders WE, Naughton MJ, et al: Isolation and

Wegman P, Vainikka L, Stal O, Nordenskjold B, Skoog L, et al: Genotype of metabolic

Wei Yan, Qing Jackie Cao, Richard B. Arenas, Brooke Bentley & Rong Shao: GATA3 Inhibits

Weigel RJ & deConinck EC: Transcriptional control of estrogen receptor in estrogen

Weigel NL & Zhang Y: Ligand-independent activation of steroid hormone receptors. J Mol

Wheelock MJ & Johnson KR: Cadherins as modulators of cellular phenotype. Annu Rev Cell

Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y & Johnson KR: Cadherin switching. J Cell

Williams C, Edvardsson K, Lewandowski SA, Ström A & Gustafsson JA: A genome-wide

Wu Y, Deng J, Rychahou PG, et al: Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell 15: 416-428, 2009. Xue C, Plieth D, Venkov C, et al: The gatekeeper effect of epithelial-mesenchymal transition

study of the repressive effects of estrogen receptor beta on estrogen receptor alpha

regulates the frequency of breast cancer metastasis. Cancer Res 63: 3386-3394, 2003.

receptor-negative breast carcinoma. Cancer Res 53:3472–3474, 1993.

signaling in breast cancer cells. Oncogene 27:1019–1032, 2008

Voduc D, Cheang M & Nielsen T: Cancer Epidemiol. Biomarkers Prev 17: 365–373, 2008. Vyhlidal C, Samudio I, Kladde M & Safe S: Transcriptional activation of transforming

response element half-site. Mol Endocrinol 24: 329–338, 2000.

antagonists. Cancer Res. 68: 5628–5638, 2008.

resistance of human breast cancer cells. EMBO J 17, 2799–2808, 1998. Vandewalle C, Comijn J, De Craene B, Vermassen P, Bruyneel E, et al: SIP1/ZEB2 induces

33: 6566-6578, 2005.

10:227- 39, 2006.

5009, 2007.

Res. 66: 2778–2784, 2006.

Med 76: 469–479, 1998.

Sci 121: 727-732, 2008.

Dev Biol 19: 207-235, 2003.

Breast Cancer Res 7:R284–290, 2005.

Transition. J Biol Chem 285 (18): 14042–14051, 2010

Metastasis 25: 657–663, 2008.

Identification of BCAR3 by a random search for genes involved in antiestrogen

EMT by repressing genes of different epithelial cell-cell junctions. Nucl Acids Res

dynamic EMT and MET associated with colorectal cancer progression. Clin Exp

growth factor by estradiol: requirement for both a GC-rich site and an estrogen

tumor formation, and late events in metastasis in epithelial cells. Cancer Cell

regulated in response to therapeutic challenge and promotes resistance to estrogen

inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. Cancer

molecular profiling of bone marrow micrometastases identifies TWIST1 as a marker of early tumor relapse in breast cancer patients. Clin Cancer Res 13:5001-

enzymes and the benet of tamoxifen in postmenopausal breast cancer patients.

Breast Cancer Metastasis through the Reversal of Epithelial Mesenchymal


Song RX, McPherson RA, Adam L, Bao Y, Shupnik M, et al: Linkage of rapid estrogen action

Song RX, Barnes CJ, Zhang Z, Bao Y, Kumar R & Santen RJ: The role of Shc and insulin-like

Speirs V, Parkes AT, Kerin MJ, Walton DS, Carleton PJ, Fox JN & Atkin SL: Co expression of

Sphyris N & Mani SA: The importance of the epithelial-mesenchymal transition in breast

Storci G, Sansone P, Trere D, et al: The basal-like breast carcinoma phenotype is regulated

Ström A, Hartman J, Foster JS, Kietz S, Wimalasena J &Gustafsson JA: Estrogen receptor

Stylianou S, Clarke RB & Brennan K: Aberrant activation of notch signalling in human

Tang B, Yoo N, Vu M, et al: Transforming growth factor- β can suppress tumorigenesis

Tavazoie SF, Alarcón C, Oskarsson T, Padua D, Wang Q, et al: Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451:147–152, 2008. Thiery JP: Epithelial-mesenchymal transitions in tumor progression. Nat Rev Cancer 2: 442–

Thiery JP: Epithelial-mesenchymal transitions in development and pathologies. Curr Opin

Thiery JP, Acloque H, Huang RY & Nieto MA. Epithelial–mesenchymal transitions in

Thompson EW & Williams ED. EMT and MET in carcinoma- clinical observations, regulatory pathways and new models. Clin Exp Metastasis 25(6):591–2, 2008. Thuault S, Valcourt U, Petersen M, Manfioletti G, Heldin C H & Moustakas A: Transforming

Trimboli AJ, Fukino K, de Bruin A, Wei G, Shen L, Tanner SM, et al: Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res 68: 937-945, 2008. Umayahara Y, Kawamori R, Watada H, Imano E, Iwama N, et al: Estrogen regulation of the

growth factor-beta employs HMGA2 to elicit epithelial- mesenchymal transition. J

insulin-like growth factor I gene transcription involves an AP-1 enhancer. J Biol

cancer. Curr Breast Cancer Rep 1: 229-237, 2009.

by Slug gene expression. J Pathol 214: 25-37, 2008.

T47D. Proc Natl Acad Sci USA 101:1566-1571, 2004.

development and disease. Cell 139(5):871–90, 2009.

breast cancer. Cancer Res 66: 1517-1525, 2006.

to the plasma membrane. Proc Natl Acad Sci USA 101:2076–2081, 2004. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, et al: Repeated observation of breast

Endocrinol 16:116–127, 2002b.

100: 8418-8423, 2003.

Res 59: 525-528, 1999.

107:15449-15454, 2010.

Cell Biol 15: 740-746, 2003.

Cell Biol 174: 175-83, 2006

Chem 269:16433-16442, 1994.

454, 2002.

to MAPK activation by ERalpha-Shc association and Shc pathway activation. Mol

growth factor 1 receptor in mediating the translocation of estrogen receptor alpha

tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA

estrogen receptor α and β: poor prognostic factors in human breast cancer? Cancer

beta inhibits 17beta-estradiol-stimulated proliferation of the breast cancer cell line

through effects on the putative cancer stem or early progenitor cell and committed progeny in a breast cancer xenograft model. Cancer Res 67(18):8643–8652, 2007. Taube JH, Herschkowitz JI, Komurov K, Zhou AY, Gupta S et al: Core epithelial-to-

mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci USA


**23** 

*Ireland* 

**Junctional Adhesion Molecules (JAMs)** 

Worldwide, breast cancer remains a leading cause of death amongst women. Annually, it is estimated that breast cancer is diagnosed in over a million women (Kasler *et al*., 2009) with over 450,000 deaths worldwide (Tirona *et al*., 2010). The incidence of the disease is highest in economically-developed countries, with lower rates in developing countries. Despite continual advances in breast cancer care which have led to reduced mortality, however, the incidence of the disease is still rising. The decrease in breast cancer-specific mortality has been attributed to improvements in screening techniques which permit earlier detection, surgical and radiotherapy interventions, better understanding of disease pathogenesis and utilization of traditional chemotherapies in a more efficacious manner. Consequently, early stage breast cancer is now a curable disease while advanced breast cancer remains a

Breast cancer is a heterogeneous disease encompassing many subtypes, which differ both in terms of their molecular backgrounds and clinical prognosis. These breast cancer subtypes range from pre-invasive early stage disease to advanced invasive disease. The simplest classifications of disease subdivide breast cancer into pre-invasive and invasive forms; with the pre-invasive forms being ductal carcinoma *in situ* (DCIS) and lobular carcinoma *in situ* (LCIS). Carcinoma *in situ* is proliferation of cancer cells within the epithelial tissue without invasion of the surrounding stromal tissue (Bland & Copeland, 1998). DCIS arises in the terminal ductal lobular units (TDLU) and in extra-lobular ducts while LCIS occurs in the breast lobules, and is recognisable histopathologically by the presence of populations of aberrant cells with small nuclei (Hanby & Hughes, 2008). Invasive breast cancers are subclassified into invasive ductal breast cancer, invasive lobular breast cancer, inflammatory breast cancer and Paget's disease. Invasive ductal carcinoma (IDC) is the most common form

DCIS is frequently considered as an obligate precursor to IDC, progressing from lower to higher grades and then onto invasive cancer with progressive accumulation of genomic changes (Farabegoli *et al*., 2002). However it has alternately been suggested that there exist genetically-distinct subgroups of DCIS, only some of which have the potential to progress to invasion (Shackney & Silverman, 2003). Long-term natural history studies of DCIS have provided supportive evidence for both possibilities (Page *et al*., 1995; Collins *et al*., 2005; Sanders *et al*., 2005). Despite such controversies, the large extent to which the genome is

of invasive breast cancer, accounting for around 85% of all cases.

**1. Introduction** 

significant clinical problem.

**1.1 Global incidence of breast cancer** 

**- New Players in Breast Cancer?** 

Gozie Offiah, Kieran Brennan and Ann M. Hopkins *Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin* 

