Navegar

Colección

Datos Estadísticas

Artículo

Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

Abstract:

The receptor tyrosine kinase Ret, a key gain-of-function mutated oncoprotein in thyroid carcinomas, has recently been implicated in other cancer types. While Ret copy number gains and mutations have been reported at low frequencies in breast tumors, we and others have reported that Ret is overexpressed in about 40% of human tumors and this correlates with poor patient prognosis. Ret activation regulates numerous intracellular pathways related to proliferation and inflammation, but it is not known whether abnormal Ret expression is sufficient to induce mammary carcinomas. Using a novel doxycycline-inducible transgenic mouse model with the MMTV promoter controlling Ret expression, we show that overexpression of wild-type Ret in the mammary epithelium produces mammary tumors, displaying a morphology that recapitulates characteristics of human luminal breast tumors. Ret-evoked tumors are estrogen receptor positive and negative for progesterone receptor. Moreover, tumors rapidly regress after doxycycline withdrawal, indicating that Ret is the driving oncoprotein. Using next-generation sequencing, we examined the levels of transcripts in these tumors, confirming a luminal signature. Ret-evoked tumors have been passaged in mice and used to test novel therapeutic approaches. Importantly, we have determined that tumors are resistant to endocrine therapy, but respond successfully to treatment with a Ret kinase inhibitor. Our data provide the first compelling evidence for an oncogenic role of non-mutated Ret in the mammary gland and are an incentive for clinical development of Ret as a cancer biomarker and therapeutic target. © 2018, Macmillan Publishers Limited, part of Springer Nature.

Registro:

Documento: Artículo
Título:Chronic expression of wild-type Ret receptor in the mammary gland induces luminal tumors that are sensitive to Ret inhibition
Autor:Gattelli, A.; García Solá, M.E.; Roloff, T.C.; Cardiff, R.D.; Kordon, E.C.; Chodosh, L.A.; Hynes, N.E.
Filiación:Universidad de Buenos Aires (UBA), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
CONICET-UBA, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Buenos Aires, 1428 CABA, Argentina
Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, Basel, CH-4058, Switzerland
Pathology and Laboratory Medicine, Center for Genomic Pathology, School of Medicine, University of California Davis (UCD), County Rd. 98 & Hutchison Dr, Davis, United States
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania (Upenn), 614 BRB II/III, 421 Curie Blvd, Philadelphia, United States
University of Basel, Basel, CH-4002, Switzerland
Palabras clave:doxycycline; protein Ret; protein tyrosine kinase inhibitor; progesterone receptor; protein Ret; RET protein, human; adult; animal cell; animal experiment; animal model; animal tissue; Article; breast epithelium; breast tumor; cancer hormone therapy; controlled study; drug targeting; enzyme inhibition; enzyme regulation; estrogen receptor positive breast cancer; female; human; human tissue; mouse; Mouse mammary tumor virus; next generation sequencing; nonhuman; priority journal; progesterone receptor positive breast cancer; protein expression; therapy resistance; wild type; animal; breast tumor; experimental mammary neoplasm; mammary gland; MCF-7 cell line; metabolism; transgenic mouse; tumor cell line; Animals; Breast Neoplasms; Cell Line, Tumor; Female; Humans; Mammary Glands, Human; Mammary Neoplasms, Animal; MCF-7 Cells; Mice; Mice, Transgenic; Proto-Oncogene Proteins c-ret; Receptors, Progesterone
Año:2018
Volumen:37
Número:29
Página de inicio:4046
Página de fin:4054
DOI: http://dx.doi.org/10.1038/s41388-018-0235-y
Título revista:Oncogene
Título revista abreviado:Oncogene
ISSN:09509232
CODEN:ONCNE
CAS:doxycycline, 10592-13-9, 17086-28-1, 564-25-0, 94088-85-4; protein Ret, 154251-46-4, 158709-11-6; Proto-Oncogene Proteins c-ret; Receptors, Progesterone; RET protein, human
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09509232_v37_n29_p4046_Gattelli

Referencias:

  • Hynes, N.E., Watson, C.J., Mammary gland growth factors: roles in normal development and in cancer (2010) Cold Spring Harb Perspect Biol, 2, p. a003186. , PID: 20554705
  • Grieco, M., Santoro, M., Berlingieri, M.T., Melilo, R.M., Donghi, R., Bongarzone, I., PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas (1990) Cell, 60, pp. 557-563. , PID: 2406025
  • Kohno, T., Ichikawa, H., Totoki, Y., Yasuda, K., Hiramoto, M., Nammo, T., KIF5B-RET fusions in lung adenocarcinoma (2012) Nat Med, 18, pp. 375-377. , PID: 22327624
  • Stransky, N., Cerami, E., Schalm, S., Kim, J.L., Lengauer, C., The landscape of kinase fusions in cancer (2014) Nat Commun, 5. , PID: 25204415
  • Nik-Zainal, S., Davies, H., Staaf, J., Ramakrishna, M., Glodzik, D., Zou, X., Landscape of somatic mutations in 560 breast cancer whole-genome sequences (2016) Nature, 534, pp. 47-54. , PID: 27135926
  • Boulay, A., Breuleux, M., Stephan, C., Fux, C., Brisken, C., Fiche, M., The Ret receptor tyrosine kinase pathway functionally interacts with the ERalpha pathway in breast cancer (2008) Cancer Res, 68, pp. 3743-3751. , PID: 18483257
  • Gattelli, A., Nalvarte, I., Boulay, A., Roloff, T.C., Schreiber, M., Carragher, N., Ret inhibition decreases growth and metastatic potential of estrogen receptor positive breast cancer cells (2013) EMBO Mol Med, 5, pp. 1335-1350. , PID: 23868506
  • Esseghir, S., Todd, S.K., Hunt, T., Poulsom, R., Plaza-Menacho, I., Reis-Filho, J.S., A role for glial cell derived neurotrophic factor induced expression by inflammatory cytokines and RET/GFR alpha 1 receptor up-regulation in breast cancer (2007) Cancer Res, 67, pp. 11732-11741. , PID: 18089803
  • Plaza-Menacho, I., Morandi, A., Robertson, D., Pancholi, S., Drury, S., Dowsett, M., Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance (2010) Oncogene, 29, pp. 4648-4657. , PID: 20531297
  • Spanheimer, P.M., Park, J.M., Askeland, R.W., Kulak, M.V., Woodfield, G.W., De Andrade, J.P., Inhibition of Ret increases the efficacy of antiestrogen and is a novel treatment strategy for luminal breast cancer (2014) Clin Cancer Res, 20, pp. 2115-2125. , PID: 24526731
  • Gunther, E.J., Belka, G.K., Wertheim, G.B., Wang, J., Hartman, J.L., Boxer, R.B., A novel doxycycline-inducible system for the transgenic analysis of mammary gland biology (2002) FASEB J, 16, pp. 283-292. , PID: 11874978
  • Moody, S.E., Sarkisian, C.J., Hahn, K.T., Gunther, E.J., Pickup, S., Dugan, K.D., Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis (2002) Cancer Cell, 2, pp. 451-461. , PID: 12498714
  • Sarkisian, J.C., Keister, B.A., Stairs, D.B., Boxer, R.B., Moody, S.E., Chodosh, L.A., Dose-dependent oncogene-induced senescence in vivo and its evasion during mamary tumorigenesis (2007) Nat Cell Biol, 9, pp. 493-505. , PID: 17450133
  • Woodfield, G.W., Chen, Y., Bair, T.B., Domann, F.E., Weigel, J., Identification of primary gene targets of TFAP2C in hormone responsive breast carcinoma cells (2010) Genes Chrom Cancer, 49, pp. 948-962. , PID: 20629094
  • Morandi, A., Martin, L.A., Gao, Q., Pancholi, S., Mackay, A., Robertson, D., GDNF-Ret signalling in ER-positive breast cancers is a key determinant of response and resistance to aromatase inhibitors (2013) Cancer Res, 73, pp. 3783-3795. , PID: 23650283
  • Cardiff, R.D., Wellings, S.R., The comparative pathology of human and mouse mammary glands (1999) J Mammary Gland Biol Neoplasia, 4, pp. 105-122. , PID: 10219910
  • Iwamoto, T., Takahashi, M., Ito, M., Hamaguchi, M., Isobe, K., Misawa, N., Oncogenicity of the ret transforming gene in MMTV/ret transgenic mice (1990) Oncogene, 5, pp. 535-542. , PID: 1691479
  • Parker, J.S., Mullins, M., Cheang, M.C., Leung, S., Voduc, D., Vickery, T., Supervised risk predictor of breast cancer based on intrinsic subtypes (2009) J Clin Oncol, 27, pp. 1160-1167. , PID: 19204204
  • Avalle, L., Pensa, S., Regis, G., Novelli, F., Poli, V., Stat1 and Stat3 in tumorigenesis. A matter of balance (2012) JAK-STAT, 1, pp. 65-72. , PID: 24058752
  • Chan, S.R., Vermi, W., Luo, J., Lucini, L., Rickert, C., Fowler, A.M., Stat1-deficient mice spontaneously develop estrogen receptor a-positive luminal mammary carcinomas (2012) Brest Cancer Res, 14, p. R16
  • Rakha, E.A., El-Sayed, M.E., Green, A.R., Paish, E.C., Powe, D.G., Gee, J., Biologic and clinical characteristics of breast cancer with single hormone receptor positive phenotype (2007) J Clin Oncol, 25, pp. 4772-4778. , PID: 17876012
  • Akeno-Stuart, N., Croyle, M., Knauf, J.A., Malaguarnera, R., Vitagliano, D., Santoro, M., The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells (2007) Cancer Res, 67, pp. 6956-6964. , PID: 17638907
  • Kohno, T., Tsuta, K., Tsuchihara, K., Nakaodu, T., Yoh, K., Goto, K., Ret fusion gene: Translation to personalized lung cancer therapy (2013) Cancer Sci, 104, pp. 1396-1400. , PID: 23991695
  • Kang, J., Qian, P.X., Pandey, V., Perry, J.K., Miller, L.D., Liu, E.T., Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma (2010) Oncogene, 31, p. 402
  • Baselga, J., Campone, M., Piccart, M., Burris, H.A., Ruggo, H.S., Sahmoud, T., Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer (2012) N Engl J Med, 366, pp. 520-529. , PID: 22149876

Citas:

---------- APA ----------
Gattelli, A., García Solá, M.E., Roloff, T.C., Cardiff, R.D., Kordon, E.C., Chodosh, L.A. & Hynes, N.E. (2018) . Chronic expression of wild-type Ret receptor in the mammary gland induces luminal tumors that are sensitive to Ret inhibition. Oncogene, 37(29), 4046-4054.
http://dx.doi.org/10.1038/s41388-018-0235-y
---------- CHICAGO ----------
Gattelli, A., García Solá, M.E., Roloff, T.C., Cardiff, R.D., Kordon, E.C., Chodosh, L.A., et al. "Chronic expression of wild-type Ret receptor in the mammary gland induces luminal tumors that are sensitive to Ret inhibition" . Oncogene 37, no. 29 (2018) : 4046-4054.
http://dx.doi.org/10.1038/s41388-018-0235-y
---------- MLA ----------
Gattelli, A., García Solá, M.E., Roloff, T.C., Cardiff, R.D., Kordon, E.C., Chodosh, L.A., et al. "Chronic expression of wild-type Ret receptor in the mammary gland induces luminal tumors that are sensitive to Ret inhibition" . Oncogene, vol. 37, no. 29, 2018, pp. 4046-4054.
http://dx.doi.org/10.1038/s41388-018-0235-y
---------- VANCOUVER ----------
Gattelli, A., García Solá, M.E., Roloff, T.C., Cardiff, R.D., Kordon, E.C., Chodosh, L.A., et al. Chronic expression of wild-type Ret receptor in the mammary gland induces luminal tumors that are sensitive to Ret inhibition. Oncogene. 2018;37(29):4046-4054.
http://dx.doi.org/10.1038/s41388-018-0235-y