Browsing by Subject "ESTROGEN-RECEPTOR"

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  • Varga, Zsuzsanna; Lebeau, Annette; Bu, Hong; Hartmann, Arndt; Penault-Llorca, Frederique; Guerini-Rocco, Elena; Schraml, Peter; Symmans, Fraser; Stoehr, Robert; Teng, Xiaodong; Turzynski, Andreas; von Wasielewski, Reinhard; Guertler, Claudia; Laible, Mark; Schlombs, Kornelia; Joensuu, Heikki; Keller, Thomas; Sinn, Peter; Sahin, Ugur; Bartlett, John; Viale, Giuseppe (2017)
    Background: Accurate determination of the predictive markers human epidermal growth factor receptor 2 (HER2/ERBB2), estrogen receptor (ER/ESR1), progesterone receptor (PgR/PGR), and marker of proliferation Ki67 (MKI67) is indispensable for therapeutic decision making in early breast cancer. In this multicenter prospective study, we addressed the issue of inter- and intrasite reproducibility using the recently developed reverse transcription-quantitative real-time polymerase chain reaction-based MammaTyper (R) test. Methods: Ten international pathology institutions participated in this study and determined messenger RNA expression levels of ERBB2, ESR1, PGR, and MKI67 in both centrally and locally extracted RNA from formalin-fixed, paraffin-embedded breast cancer specimens with the MammaTyper (R) test. Samples were measured repeatedly on different days within the local laboratories, and reproducibility was assessed by means of variance component analysis, Fleiss' kappa statistics, and interclass correlation coefficients (ICCs). Results: Total variations in measurements of centrally and locally prepared RNA extracts were comparable; therefore, statistical analyses were performed on the complete dataset. Intersite reproducibility showed total SDs between 0.21 and 0.44 for the quantitative single-marker assessments, resulting in ICC values of 0.980-0.998, demonstrating excellent agreement of quantitative measurements. Also, the reproducibility of binary single-marker results (positive/negative), as well as the molecular subtype agreement, was almost perfect with kappa values ranging from 0.90 to 1.00. Conclusions: On the basis of these data, the MammaTyper (R) has the potential to substantially improve the current standards of breast cancer diagnostics by providing a highly precise and reproducible quantitative assessment of the established breast cancer biomarkers and molecular subtypes in a decentralized workup.
  • Munne, Pauliina M.; Martikainen, Lahja; Räty, Iiris; Bertula, Kia; Nonappa; Ruuska, Janika; Ala-Hongisto, Hanna; Peura, Aino; Hollmann, Babette; Euro, Lilya; Yavuz, Kerim; Patrikainen, Linda; Salmela, Maria; Pokki, Juho; Kivento, Mikko; Väänänen, Juho; Suomi, Tomi; Nevalaita, Liina; Mutka, Minna; Kovanen, Panu; Leidenius, Marjut; Meretoja, Tuomo; Hukkinen, Katja; Monni, Outi; Pouwels, Jeroen; Sahu, Biswajyoti; Mattson, Johanna; Joensuu, Heikki; Heikkilä, Päivi; Elo, Laura L.; Metcalfe, Ciara; Junttila, Melissa R.; Ikkala, Olli; Klefström, Juha (2021)
    Breast cancer is now globally the most frequent cancer and leading cause of women's death. Two thirds of breast cancers express the luminal estrogen receptor-positive (ER alpha + ) phenotype that is initially responsive to antihormonal therapies, but drug resistance emerges. A major barrier to the understanding of the ER alpha-pathway biology and therapeutic discoveries is the restricted repertoire of luminal ER alpha + breast cancer models. The ER alpha + phenotype is not stable in cultured cells for reasons not fully understood. We examine 400 patient-derived breast epithelial and breast cancer explant cultures (PDECs) grown in various three-dimensional matrix scaffolds, finding that ER alpha is primarily regulated by the matrix stiffness. Matrix stiffness upregulates the ER alpha signaling via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation. The finding that the matrix stiffness is a central cue to the ER alpha phenotype reveals a mechanobiological component in breast tissue hormonal signaling and enables the development of novel therapeutic interventions. Subject terms: ER-positive (ER + ), breast cancer, ex vivo model, preclinical model, PDEC, stiffness, p38 SAPK. Reliable luminal estrogen receptor (ER alpha+) breast cancer models are limited. Here, the authors use patient derived breast epithelial and breast cancer explant cultures grown in several extracellular matrix scaffolds and show that ER alpha expression is regulated by matrix stiffness via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation.
  • Dai, Xiaofeng; Li, Lu; Liu, Xiuxia; Hu, Weiguo; Yang, Yankun; Bai, Zhonghu (2015)
  • Horne, Hisani N.; Oh, Hannah; Sherman, Mark E.; Palakal, Maya; Hewitt, Stephen M.; Schmidt, Marjanka K.; Milne, Roger L.; Hardisson, David; Benitez, Javier; Blomqvist, Carl; Bolla, Manjeet K.; Brenner, Hermann; Chang-Claude, Jenny; Cora, Renata; Couch, Fergus J.; Cuk, Katarina; Devilee, Peter; Easton, Douglas F.; Eccles, Diana M.; Eilber, Ursula; Hartikainen, Jaana M.; Heikkilä, Paivi; Holleczek, Bernd; Hooning, Maartje J.; Jones, Michael; Keeman, Renske; Mannermaa, Arto; Martens, John W. M.; Muranen, Taru A.; Nevanlinna, Heli; Olson, Janet E.; Orr, Nick; Perez, Jose I. A.; Pharoah, Paul D. P.; Ruddy, Kathryn J.; Saum, Kai-Uwe; Schoemaker, Minouk J.; Seynaeve, Caroline; Sironen, Reijo; Smit, Vincent T. H. B. M.; Swerdlow, Anthony J.; Tengstrom, Maria; Thomas, Abigail S.; Timmermans, A. Mieke; Tollenaar, Rob A. E. M.; Troester, Melissa A.; van Asperen, Christi J.; van Deurzen, Carolien H. M.; Van Leeuwen, Flora F.; Van'tVeer, Laura J. (2018)
    E-cadherin (CDH1) is a putative tumor suppressor gene implicated in breast carcinogenesis. Yet, whether risk factors or survival differ by E-cadherin tumor expression is unclear. We evaluated E-cadherin tumor immunohistochemistry expression using tissue microarrays of 5,933 female invasive breast cancers from 12 studies from the Breast Cancer Consortium. H-scores were calculated and case-case odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression. Survival analyses were performed using Cox regression models. All analyses were stratified by estrogen receptor (ER) status and histologic subtype. E-cadherin low cases (N = 1191, 20%) were more frequently of lobular histology, low grade, > 2 cm, and HER2-negative. Loss of E-cadherin expression (score <100) was associated with menopausal hormone use among ER-positive tumors (ever compared to never users, OR = 1.24, 95% CI = 0.97-1.59), which was stronger when we evaluated complete loss of E-cadherin (i.e. H-score = 0), OR = 1.57, 95% CI = 1.06-2.33. Breast cancer specific mortality was unrelated to E-cadherin expression in multivariable models. E-cadherin low expression is associated with lobular histology, tumor characteristics and menopausal hormone use, with no evidence of an association with breast cancer specific survival. These data support loss of E-cadherin expression as an important marker of tumor subtypes.
  • Peltonen, Johanna; Tuomainen, Katja; Sallinen, Tobias; Faress, Islam; Suleymanova, Ilida; Al-Samadi, Ahmed; Salo, Tuula; Åström, Pirjo (2020)
    Background: Tongue cancer is more common in men than in women. Yet the effects of sex steroid hormones on the behaviour of oral tongue squamous cell carcinoma (OTSCC) are not well known. Matrix metalloproteinase 8 (MMP8) is expressed in OTSCC and can degrade estrogen receptors (ERs). Materials and Methods: Western blot was used to examine the levels of ER beta in OTSCC cell lines (HSC-3 and SCC-25). We evaluated the effects of estradiol and dihydrotestosterone (DHT) on HSC-3 and SCC-25 cell migration, invasion and viability. The effect of estradiol on the invasion of MMP8-overexpressing (MMP8(+)) and empty vector HSC-3 cells was examined using 3D spheroid invasion assay. Results: Both HSC-3 and SCC-25 cells expressed ER beta. In scratch assay, estradiol, but not DHT, reduced the migration and invasion of HSC-3 and SCC-25 cells. MMP8(+) HSC-3 cells showed weaker invasion than empty vector cells, in line with previous reports. However, MMP8 overexpression did not alter the effect of estradiol on HSC-3 cell invasion in spheroid assay. Conclusion: Estradiol inhibited the migration and invasion of OTSCC cells, whereas DHT had no effect. Our data suggest that MMP8 does not modulate the effect of estradiol in OTSCC cells. However, the sex difference in OTSCC incidence might partly be due to protective actions of estradiol in epithelial cell carcinogenesis.
  • Kjällquist, Una; Erlandsson, Rikard; Tobin, Nicholas P.; Alkodsi, Amjad; Ullah, Ikram; Stalhammar, Gustav; Karlsson, Eva; Hatschek, Thomas; Hartman, Johan; Linnarsson, Sten; Bergh, Jonas (2018)
    Background: Tumor heterogeneity in breast cancer tumors is today widely recognized. Most of the available knowledge in genetic variation however, relates to the primary tumor while metastatic lesions are much less studied. Many studies have revealed marked alterations of standard prognostic and predictive factors during tumor progression. Characterization of paired primary- and metastatic tissues should therefore be fundamental in order to understand mechanisms of tumor progression, clonal relationship to tumor evolution as well as the therapeutic aspects of systemic disease. Methods: We performed full exome sequencing of primary breast cancers and their metastases in a cohort of ten patients and further confirmed our findings in an additional cohort of 20 patients with paired primary and metastatic tumors. Furthermore, we used gene expression from the metastatic lesions and a primary breast cancer data set to study the gene expression of the AKAP gene family. Results: We report that somatic mutations in A-kinase anchoring proteins are enriched in metastatic lesions. The frequency of mutation in the AKAP gene family was 10% in the primary tumors and 40% in metastatic lesions. Several copy number variations, including deletions in regions containing AKAP genes were detected and showed consistent patterns in both investigated cohorts. In a second cohort containing 20 patients with paired primary and metastatic lesions, AKAP mutations showed an increasing variant allele frequency after multiple relapses. Furthermore, gene expression profiles from the metastatic lesions (n = 120) revealed differential expression patterns of AKAPs relative to the tumor PAM50 intrinsic subtype, which were most apparent in the basal-like subtype. This pattern was confirmed in primary tumors from TCGA (n = 522) and in a third independent cohort (n = 182). Conclusion: Several studies from primary cancers have reported individual AKAP genes to be associated with cancer risk and metastatic relapses as well as direct involvement in cellular invasion and migration processes. Our findings reveal an enrichment of mutations in AKAP genes in metastatic breast cancers and suggest the involvement of AKAPs in the metastatic process. In addition, we report an AKAP gene expression pattern that consistently follows the tumor intrinsic subtype, further suggesting AKAP family members as relevant players in breast cancer biology.
  • Mohamed, Hesham; Aro, Katri; Jouhi, Lauri; Makitie, Antti; Remes, Satu; Haglund, Caj; Atula, Timo; Hagstrom, Jaana (2018)
    Hormone receptors play an important role in many types of cancers. Alongside factors associated with human papillomavirus (HPV) infection, hormonal receptors may impact the tumorigenesis of oropharyngeal cancer. This study consists of 199 consecutive oropharyngeal squamous cell carcinoma (OPSCC) patients diagnosed and treated with a curative intent. We examined androgen (AR), estrogen (ER; both alpha and beta), and progesterone receptor (PR) expressions using immunohistochemistry comparing tumor and patient characteristics. AR was expressed in 16%, PR in 27% and ER-beta in 63% of the tumors. HPV- and p16-positive tumors expressed more AR and less PR than their negative counterparts. High PR expression was associated with poor disease-specific and locoregional recurrence-free survival. AR, PR, and ER-beta are expressed in OPSCC, and AR and PR expressions are associated with HPV and p16 status. Furthermore, PR appears to have prognostic significance. This may allow us to investigate the role of anti-hormone receptors in the treatment of OPSCC.
  • Fachal, L.; Aschard, H.; Beesley, J.; Barnes, D.R.; Allen, J.; Kar, S.; Pooley, K.A.; Dennis, J.; Michailidou, K.; Turman, C.; Soucy, P.; Lemaçon, A.; Lush, M.; Tyrer, J.P.; Ghoussaini, M.; Marjaneh, M.M.; Jiang, X.; Agata, S.; Aittomäki, K.; Alonso, M.R.; Andrulis, I.L.; Anton-Culver, H.; Antonenkova, N.N.; Arason, A.; Arndt, V.; Aronson, K.J.; Arun, B.K.; Auber, B.; Auer, P.L.; Azzollini, J.; Balmaña, J.; Barkardottir, R.B.; Barrowdale, D.; Beeghly-Fadiel, A.; Benitez, J.; Bermisheva, M.; Białkowska, K.; Blanco, A.M.; Blomqvist, C.; Blot, W.; Bogdanova, N.V.; Bojesen, S.E.; Bolla, M.K.; Bonanni, B.; Borg, A.; Bosse, K.; Brauch, H.; Brenner, H.; Briceno, I.; Brock, I.W.; Brooks-Wilson, A.; Brüning, T.; Burwinkel, B.; Buys, S.S.; Cai, Q.; Caldés, T.; Caligo, M.A.; Camp, N.J.; Campbell, I.; Canzian, F.; Carroll, J.S.; Carter, B.D.; Castelao, J.E.; Chiquette, J.; Christiansen, H.; Chung, W.K.; Claes, K.B.M.; Clarke, C.L.; Mari, V.; Berthet, P.; Castera, L.; Vaur, D.; Lallaoui, H.; Bignon, Y.-J.; Uhrhammer, N.; Bonadona, V.; Lasset, C.; Révillion, F.; Vennin, P.; Muller, D.; Gomes, D.M.; Ingster, O.; Coupier, I.; Pujol, P.; Collonge-Rame, M.-A.; Mortemousque, I.; Bera, O.; Rose, M.; Baurand, A.; Bertolone, G.; Faivre, L.; Dreyfus, H.; Leroux, D.; Venat-Bouvet, L.; Bézieau, S.; Delnatte, C.; Chiesa, J.; Gilbert-Dussardier, B.; Gesta, P.; Prieur, F.P.; Bronner, M.; Sokolowska, J.; Coulet, F.; Boutry-Kryza, N.; Calender, A.; Giraud, S.; Leone, M.; Fert-Ferrer, S.; Stoppa-Lyonnet, D.; Jiao, Y.; Lesueur, F.L.; Mebirouk, N.; Barouk-Simonet, E.; Bubien, V.; Longy, M.; Sevenet, N.; Gladieff, L.; Toulas, C.; Reimineras, A.; Sobol, H.; Paillerets, B.B.-D.; Cabaret, O.; Caron, O.; Guillaud-Bataille, M.; Rouleau, E.; Belotti, M.; Buecher, B.; Caputo, S.; Colas, C.; Pauw, A.D.; Fourme, E.; Gauthier-Villars, M.; Golmard, L.; Moncoutier, V.; Saule, C.; Donaldson, A.; Murray, A.; Brady, A.; Brewer, C.; Pottinger, C.; Miller, C.; Gallagher, D.; Gregory, H.; Cook, J.; Eason, J.; Adlard, J.; Barwell, J.; Ong, K.-R.; Snape, K.; Walker, L.; Izatt, L.; Side, L.; Tischkowitz, M.; Rogers, M.T.; Porteous, M.E.; Ahmed, M.; Morrison, P.J.; Brennan, P.; Eeles, R.; Davidson, R.; Collée, M.; Cornelissen, S.; Couch, F.J.; Cox, A.; Cross, S.S.; Cybulski, C.; Czene, K.; Daly, M.B.; de la Hoya, M.; Devilee, P.; Diez, O.; Ding, Y.C.; Dite, G.S.; Domchek, S.M.; Dörk, T.; dos-Santos-Silva, I.; Droit, A.; Dubois, S.; Dumont, M.; Duran, M.; Durcan, L.; Dwek, M.; Eccles, D.M.; Engel, C.; Eriksson, M.; Evans, D.G.; Fasching, P.A.; Fletcher, O.; Floris, G.; Flyger, H.; Foretova, L.; Foulkes, W.D.; Friedman, E.; Fritschi, L.; Frost, D.; Gabrielson, M.; Gago-Dominguez, M.; Gambino, G.; Ganz, P.A.; Gapstur, S.M.; Garber, J.; García-Sáenz, J.A.; Gaudet, M.M.; Georgoulias, V.; Giles, G.; Glendon, G.; Godwin, A.K.; Goldberg, M.S.; Goldgar, D.E.; González-Neira, A.; Tibiletti, M.G.; Greene, M.H.; Grip, M.; Gronwald, J.; Grundy, A.; Guénel, P.; Hahnen, E.; Haiman, C.A.; Håkansson, N.; Hall, P.; Hamann, U.; Harrington, P.A.; Hartikainen, J.M.; Hartman, M.; He, W.; Healey, C.S.; Heemskerk-Gerritsen, B.A.M.; Heyworth, J.; Hillemanns, P.; Hogervorst, F.B.L.; Hollestelle, A.; Hooning, M.; Hopper, J.; Howell, A.; Huang, G.; Hulick, P.J.; Imyanitov, E.N.; Sexton, A.; Christian, A.; Trainer, A.; Spigelman, A.; Fellows, A.; Shelling, A.; Fazio, A.D.; Blackburn, A.; Crook, A.; Meiser, B.; Patterson, B.; Clarke, C.; Saunders, C.; Hunt, C.; Scott, C.; Amor, D.; Marsh, D.; Edkins, E.; Salisbury, E.; Haan, E.; Neidermayr, E.; Macrea, F.; Farshid, G.; Lindeman, G.; Chenevix-Trench, G.; Mann, G.; Giles, G.; Gill, G.; Thorne, H.; Campbell, I.; Hickie, I.; Winship, I.; Flanagan, J.; Kollias, J.; Visvader, J.; Stone, J.; Taylor, J.; Burke, J.; Saunus, J.; Forbes, J.; Hopper, J.; Beesley, J.; Kirk, J.; French, J.; Tucker, K.; Wu, K.; Phillips, K.; Lipton, L.; Andrews, L.; Lobb, L.; Walker, L.; Kentwell, M.; Spurdle, M.; Cummings, M.; Gleeson, M.; Harris, M.; Jenkins, M.; Young, M.A.; Delatycki, M.; Wallis, M.; Burgess, M.; Price, M.; Brown, M.; Southey, M.; Bogwitz, M.; Field, M.; Friedlander, M.; Gattas, M.; Saleh, M.; Hayward, N.; Pachter, N.; Cohen, P.; Duijf, P.; James, P.; Simpson, P.; Fong, P.; Butow, P.; Williams, R.; Kefford, R.; Scott, R.; Milne, R.L.; Balleine, R.; Dawson, S.–J.; Lok, S.; O’Connell, S.; Greening, S.; Nightingale, S.; Edwards, S.; Fox, S.; McLachlan, S.-A.; Lakhani, S.; Antill, Y.; Aalfs, C.; Meijers-Heijboer, H.; van Engelen, K.; Gille, H.; Boere, I.; Collée, M.; van Deurzen, C.; Hooning, M.; Obdeijn, I.-M.; van den Ouweland, A.; Seynaeve, C.; Siesling, S.; Verloop, J.; van Asperen, C.J.; Devilee, P.; van Cronenburg, T.; Blok, R.; de Boer, M.; Garcia, E.G.; Adank, M.; Hogervorst, F.; Jenner, D.; van Leeuwen, F.; Rookus, M.; Russell, N.; Schmidt, M.; van den Belt-Dusebout, S.; Kets, C.; Mensenkamp, A.; de Bock, T.; van der Hout, A.; Mourits, M.; Oosterwijk, J.; Ausems, M.; Koudijs, M.; Clarke, C.; Marsh, D.; Scott, R.; Baxter, R.; Yip, D.; Carpenter, J.; Davis, A.; Pathmanathan, N.; Simpson, P.; Graham, D.; Sachchithananthan, M.; Isaacs, C.; Iwasaki, M.; Jager, A.; Jakimovska, M.; Jakubowska, A.; James, P.A.; Janavicius, R.; Jankowitz, R.C.; John, E.M.; Johnson, N.; Jones, M.E.; Jukkola-Vuorinen, A.; Jung, A.; Kaaks, R.; Kang, D.; Kapoor, P.M.; Karlan, B.Y.; Keeman, R.; Kerin, M.J.; Khusnutdinova, E.; Kiiski, J.I.; Kirk, J.; Kitahara, C.M.; Ko, Y.-D.; Konstantopoulou, I.; Kosma, V.-M.; Koutros, S.; Kubelka-Sabit, K.; Kwong, A.; Kyriacou, K.; Laitman, Y.; Lambrechts, D.; Lee, E.; Leslie, G.; Lester, J.; Lesueur, F.; Lindblom, A.; Lo, W.-Y.; Long, J.; Lophatananon, A.; Loud, J.T.; Lubiński, J.; MacInnis, R.J.; Maishman, T.; Makalic, E.; Mannermaa, A.; Manoochehri, M.; Manoukian, S.; Margolin, S.; Martinez, M.E.; Matsuo, K.; Maurer, T.; Mavroudis, D.; Mayes, R.; McGuffog, L.; McLean, C.; Mebirouk, N.; Meindl, A.; Miller, A.; Miller, N.; Montagna, M.; Moreno, F.; Muir, K.; Mulligan, A.M.; Muñoz-Garzon, V.M.; Muranen, T.A.; Narod, S.A.; Nassir, R.; Nathanson, K.L.; Neuhausen, S.L.; Nevanlinna, H.; Neven, P.; Nielsen, F.C.; Nikitina-Zake, L.; Norman, A.; Offit, K.; Olah, E.; Olopade, O.I.; Olsson, H.; Orr, N.; Osorio, A.; Pankratz, V.S.; Papp, J.; Park, S.K.; Park-Simon, T.-W.; Parsons, M.T.; Paul, J.; Pedersen, I.S.; Peissel, B.; Peshkin, B.; Peterlongo, P.; Peto, J.; Plaseska-Karanfilska, D.; Prajzendanc, K.; Prentice, R.; Presneau, N.; Prokofyeva, D.; Pujana, M.A.; Pylkäs, K.; Radice, P.; Ramus, S.J.; Rantala, J.; Rau-Murthy, R.; Rennert, G.; Risch, H.A.; Robson, M.; Romero, A.; Rossing, M.; Saloustros, E.; Sánchez-Herrero, E.; Sandler, D.P.; Santamariña, M.; Saunders, C.; Sawyer, E.J.; Scheuner, M.T.; Schmidt, D.F.; Schmutzler, R.K.; Schneeweiss, A.; Schoemaker, M.J.; Schöttker, B.; Schürmann, P.; Scott, C.; Scott, R.J.; Senter, L.; Seynaeve, C.M.; Shah, M.; Sharma, P.; Shen, C.-Y.; Shu, X.-O.; Singer, C.F.; Slavin, T.P.; Smichkoska, S.; Southey, M.C.; Spinelli, J.J.; Spurdle, A.B.; Stone, J.; Stoppa-Lyonnet, D.; Sutter, C.; Swerdlow, A.J.; Tamimi, R.M.; Tan, Y.Y.; Tapper, W.J.; Taylor, J.A.; Teixeira, M.R.; Tengström, M.; Teo, S.H.; Terry, M.B.; Teulé, A.; Thomassen, M.; Thull, D.L.; Tischkowitz, M.; Toland, A.E.; Tollenaar, R.A.E.M.; Tomlinson, I.; Torres, D.; Torres-Mejía, G.; Troester, M.A.; Truong, T.; Tung, N.; Tzardi, M.; Ulmer, H.-U.; Vachon, C.M.; van Asperen, C.J.; van der Kolk, L.E.; van Rensburg, E.J.; Vega, A.; Viel, A.; Vijai, J.; Vogel, M.J.; Wang, Q.; Wappenschmidt, B.; Weinberg, C.R.; Weitzel, J.N.; Wendt, C.; Wildiers, H.; Winqvist, R.; Wolk, A.; Wu, A.H.; Yannoukakos, D.; Zhang, Y.; Zheng, W.; Hunter, D.; Pharoah, P.D.P.; Chang-Claude, J.; García-Closas, M.; Schmidt, M.K.; Milne, R.L.; Kristensen, V.N.; French, J.D.; Edwards, S.L.; Antoniou, A.C.; Chenevix-Trench, G.; Simard, J.; Easton, D.F.; Kraft, P.; Dunning, A.M.; Collaborators, GEMO Study; Collaborators, EMBRACE; Investigators, KConFab; Investigators, HEBON; Investigators, ABCTB (2020)
    Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions. Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
  • Aure, Miriam Ragle; Leivonen, Suvi-Katri; Fleischer, Thomas; Zhu, Qian; Overgaard, Jens; Alsner, Jan; Tramm, Trine; Louhimo, Riku; Alnaes, Grethe I. Grenaker; Perala, Merja; Busato, Florence; Touleimat, Nizar; Tost, Joerg; Borresen-Dale, Anne-Lise; Hautaniemi, Sampsa; Troyanskaya, Olga G.; Lingjaerde, Ole Christian; Sahlberg, Kristine Kleivi; Kristensen, Vessela N. (2013)
  • Karthik, Govindasamy-Muralidharan; Rantalainen, Mattias; Stalhammar, Gustav; Lovrot, John; Ullah, Ikram; Alkodsi, Amjad; Ma, Ran; Wedlund, Lena; Lindberg, Johan; Frisell, Jan; Bergh, Jonas; Hartman, Johan (2017)
    Background: Transcriptomic profiling of breast tumors provides opportunity for subtyping and molecular-based patient stratification. In diagnostic applications the specimen profiled should be representative of the expression profile of the whole tumor and ideally capture properties of the most aggressive part of the tumor. However, breast cancers commonly exhibit intra-tumor heterogeneity at molecular, genomic and in phenotypic level, which can arise during tumor evolution. Currently it is not established to what extent a random sampling approach may influence molecular breast cancer diagnostics. Methods: In this study we applied RNA-sequencing to quantify gene expression in 43 pieces (2-5 pieces per tumor) from 12 breast tumors (Cohort 1). We determined molecular subtype and transcriptomic grade for all tumor pieces and analysed to what extent pieces originating from the same tumors are concordant or discordant with each other. Additionally, we validated our finding in an independent cohort consisting of 19 pieces (2-6 pieces per tumor) from 6 breast tumors (Cohort 2) profiled using microarray technique. Exome sequencing was also performed on this cohort, to investigate the extent of intra-tumor genomic heterogeneity versus the intra-tumor molecular subtype classifications. Results: Molecular subtyping was consistent in 11 out of 12 tumors and transcriptomic grade assignments were consistent in 11 out of 12 tumors as well. Molecular subtype predictions revealed consistent subtypes in four out of six patients in this cohort 2. Interestingly, we observed extensive intra-tumor genomic heterogeneity in these tumor pieces but not in their molecular subtype classifications. Conclusions: Our results suggest that macroscopic intra-tumoral transcriptomic heterogeneity is limited and unlikely to have an impact on molecular diagnostics for most patients.
  • Jacquemet, Guillaume; Baghirov, Habib; Georgiadou, Maria; Sihto, Harri; Peuhu, Emilia; Cettour-Janet, Pierre; He, Tao; Perala, Merja; Kronqvist, Pauliina; Joensuu, Heikki; Ivaska, Johanna (2016)
    Mounting in vitro, in vivo and clinical evidence suggest an important role for filopodia in driving cancer cell invasion. Using a high-throughput microscopic-based drug screen, we identify FDA-approved calcium channel blockers (CCBs) as potent inhibitors of filopodia formation in cancer cells. Unexpectedly, we discover that L-type calcium channels are functional and frequently expressed in cancer cells suggesting a previously unappreciated role for these channels during tumorigenesis. We further demonstrate that, at filopodia, L-type calcium channels are activated by integrin inside-out signalling, integrin activation and Src. Moreover, L-type calcium channels promote filopodia stability and maturation into talin-rich adhesions through the spatially restricted regulation of calcium entry and subsequent activation of the protease calpain-1. Altogether we uncover a novel and clinically relevant signalling pathway that regulates filopodia formation in cancer cells and propose that cycles of filopodia stabilization, followed by maturation into focal adhesions, directs cancer cell migration and invasion.
  • Khan, Sofia; Fagerholm, Rainer; Kadalayil, Latha; Tapper, William; Aittomäki, Kristiina; Liu, Jianjun; Blomqvist, Carl; Eccles, Diana; Nevanlinna, Heli (2018)
    The majority of breast cancers are driven by the female hormone oestrogen via oestrogen receptor (ER) alpha. ER-positive patients are commonly treated with adjuvant endocrine therapy, however, resistance is a common occurrence and aside from ER-status, no unequivocal predictive biomarkers are currently in clinical use. In this study, we aimed to identify constitutional genetic variants influencing breast cancer survival among ER-positive patients and specifically, among endocrine-treated patients. We conducted a meta-analysis of three genome-wide association studies comprising in total 3,136 patients with ER-positive breast cancer of which 2,751 had received adjuvant endocrine therapy. We identified a novel locus (rs992531 at 8p21.2) associated with reduced survival among the patients with ER-positive breast cancer (P = 3.77 x 10(-8)). Another locus (rs7701292 at 5q21.3) was associated with reduced survival among the endocrine-treated patients (P = 2.13 x 10(-8)). Interaction analysis indicated that the survival association of rs7701292 is treatment-specific and independent of conventional prognostic markers. In silico functional studies suggest plausible biological mechanisms for the observed survival associations and a functional link between the putative target genes of the rs992531 and rs7701292 (RHOBTB2 and RAB9P1, respectively). We further explored the genetic interaction between rs992531 and rs7701292 and found a significant, treatment-specific interactive effect on survival among ER-positive, endocrine-treated patients (hazard ratio = 6.97; 95% confidence interval, 1.79-27.08, P-interaction = 0.036). This is the first study to identify a genetic interaction that specifically predicts treatment outcome. These findings may provide predictive biomarkers based on germ line genotype informing more personalized treatment selection.
  • Schmidt, Marcus; Weyer-Elberich, Veronika; Hengstler, Jan G.; Heimes, Anne-Sophie; Almstedt, Katrin; Gerhold-Ay, Aslihan; Lebrecht, Antje; Battista, Marco J.; Hasenburg, Annette; Sahin, Ugur; Kalogeras, Konstantine T.; Kellokumpu-Lehtinen, Pirkko-Liisa; Fountzilas, George; Wirtz, Ralph M.; Joensuu, Heikki (2018)
    Background: The clinical importance of tumor-infiltrating cluster of differentiation 4 (CD4) T cells is incompletely understood in early breast cancer. We investigated the clinical significance of CD4, forkhead box P3 (FOXP3), and B cell attracting chemokine leukocyte chemoattractant-ligand (C-X-C motif) 13 (CXCL13) in early breast cancer. Methods: The study is based on the patient population of the randomized FinHer trial, where 1010 patients with early breast cancer were randomly allocated to adjuvant chemotherapy containing either docetaxel or vinorelbine, and human epidermal growth factor receptor 2 (HER2)-positive patients were also allocated to trastuzumab or no trastuzumab. Breast cancer CD4, FOXP3, and CXCL13 contents were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR), and their influence on distant disease-free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan-Meier estimates in the entire cohort and in selected molecular subgroups. Interactions between variables were analyzed using Cox regression. The triple-negative breast cancer (TNBC) subset of the HE10/97 randomized trial was used for confirmation. Results: High CXCL13 was associated with favorable DDFS in univariable analysis, and independently in multivariable analysis (HR 0.44, 95% CI 0.29-0.67, P Conclusions: The results provide a high level of evidence that humoral immunity influences the survival outcomes of patients with early breast cancer, in particular of those with TNBC.
  • Hollmen, Maija; Liu, Ping; Kurppa, Kari; Wildiers, Hans; Reinvall, Irene; Vandorpe, Thijs; Smeets, Ann; Deraedt, Karen; Vahlberg, Tero; Joensuu, Heikki; Leahy, Daniel J.; Schoffski, Patrick; Elenius, Klaus (2012)
  • Kibble, Milla; Khan, Suleiman A.; Saarinen, Niina; Iorio, Francesco; Saez-Rodriguez, Julio; Makela, Sari; Aittokallio, Tero (2016)
    Drug discovery is moving away from the single target-based approach towards harnessing the potential of polypharmacological agents that modulate the activity of multiple nodes in the complex networks of deregulations underlying disease phenotypes. Computational network pharmacology methods that use systems-level drug-response phenotypes, such as those originating from genome-wide transcriptomic profiles, have proved particularly effective for elucidating the mechanisms of action of multitargeted compounds. Here, we show, via the case study of the natural product pinosylvin, how the combination of two complementary network-based methods can provide novel, unexpected mechanistic insights. This case study also illustrates that elucidating the mechanism of action of multitargeted natural products through transcriptional response-based approaches is a challenging endeavor, often requiring multiple computational-experimental iterations.