Chronic expression of wild-type Ret receptor in the mammary gland induces luminal tumors that are sensitive to Ret inhibition
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 overexpres...
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2018
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09509232_v37_n29_p4046_Gattelli http://hdl.handle.net/20.500.12110/paper_09509232_v37_n29_p4046_Gattelli |
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paper:paper_09509232_v37_n29_p4046_Gattelli2023-06-08T15:54:51Z Chronic expression of wild-type Ret receptor in the mammary gland induces luminal tumors that are sensitive to Ret inhibition 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 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. 2018 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09509232_v37_n29_p4046_Gattelli http://hdl.handle.net/20.500.12110/paper_09509232_v37_n29_p4046_Gattelli |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Chronic expression of wild-type Ret receptor in the mammary gland induces luminal tumors that are sensitive to Ret inhibition |
| topic_facet |
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 |
| description |
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. |
| title |
Chronic expression of wild-type Ret receptor in the mammary gland induces luminal tumors that are sensitive to Ret inhibition |
| title_short |
Chronic expression of wild-type Ret receptor in the mammary gland induces luminal tumors that are sensitive to Ret inhibition |
| title_full |
Chronic expression of wild-type Ret receptor in the mammary gland induces luminal tumors that are sensitive to Ret inhibition |
| title_fullStr |
Chronic expression of wild-type Ret receptor in the mammary gland induces luminal tumors that are sensitive to Ret inhibition |
| title_full_unstemmed |
Chronic expression of wild-type Ret receptor in the mammary gland induces luminal tumors that are sensitive to Ret inhibition |
| title_sort |
chronic expression of wild-type ret receptor in the mammary gland induces luminal tumors that are sensitive to ret inhibition |
| publishDate |
2018 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09509232_v37_n29_p4046_Gattelli http://hdl.handle.net/20.500.12110/paper_09509232_v37_n29_p4046_Gattelli |
| _version_ |
1768543092460224512 |