Andrea Morani - Academia.edu (original) (raw)

Papers by Andrea Morani

Estrogen receptors (ER) are important regulators of metabolic diseases such as obesity and insuli... more Estrogen receptors (ER) are important regulators of metabolic diseases such as obesity and insulin resistance (IR). While ERa seems to have a protective role in such diseases, the function of ERb is not clear. To characterize the metabolic function of ERb, we investigated its molecular interaction with a master regulator of insulin signaling/glucose metabolism, the PPARc, in vitro and in high-fat diet (HFD)-fed ERb-/- mice (bERKO) mice. Our in vitro experiments showed that ERb inhibits ligandmediated PPARc-transcriptional activity. That resulted in a blockade of PPARc-induced adipocytic gene expression and in decreased adipogenesis. Overexpression of nuclear coactivators such as SRC1 and TIF2 prevented the ERb-mediated inhibition of PPARc activity. Consistent with the in vitro data, we observed increased PPARc activity in gonadal fat from HFD-fed bERKO mice. In consonance with enhanced PPARc activation, HFD-fed bERKO mice showed increased body weight gain and fat mass in the presenc...

Breast cancer is the most common malignancy among Swedish women. Although the mechanism behind th... more Breast cancer is the most common malignancy among Swedish women. Although the mechanism behind the tumorigenesis remains unclear, estrogen receptor α (ERα) plays an important role in the progression of breast cancer and is regarded as a target for endocrine therapy. In this thesis, focus is on the second estrogen receptor, ERβ and its function in breast cancer. In addition, the significance of the transcription factors Hes-1 and Hes-6 in breast cancer and their relation to ERα has been studied. By using T47D breast cancer cells with inducible ERβ expression, the role of ERβ has been characterised with respect to proliferation and cell-cycle regulation. In contrast to ERα, expression of ERβ inhibited the proliferation of 17β-estradiol (E2) treated breast cancer cells and caused significantly changed levels of cell-cycle regulators. In response to ERβ expression, the levels of the Cdk2-activating phosphatase Cdc25A as well as cyclin E and E2F1 were reduced with a subsequent decrease o...

Proceedings of the National Academy of Sciences of the United States of America, 2006

Estrogen receptor beta (ERbeta) is highly expressed in both type I and II pneumocytes as well as ... more Estrogen receptor beta (ERbeta) is highly expressed in both type I and II pneumocytes as well as bronchiolar epithelial cells. ERalpha is not detectable in the adult lung. Lungs of adult female ERbeta knockout (ERbeta-/-) mice have already been reported to have fewer alveoli and reduced elastic recoil. In this article, we report that, by 5 months of age, there are large areas of unexpanded alveoli in lungs of both male and female ERbeta-/- mice. There is increased staining for collagen and, by EM, abnormal clusters of collagen fibers are seen in the alveolar septa of ERbeta-/- mice. Immunohistochemical analysis and Western blotting with lung membrane fractions of ERbeta-/- mice revealed down-regulation of caveolin-1, increased expression of membrane type-1 metalloproteinase, matrix metalloproteinase 2 (active form), and tissue inhibitors of metalloproteinases 2. Hypoxia, measured by immunohistochemical analysis for hypoxia-inducible factor 1alpha and chemical adducts (with Hypoxypro...

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific r... more HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Insulin resistance of pregnancy involves estrogen-induced repression of muscle GLUT4 Rodrigo Palazzo de Almeida Barros, Andrea Morani, Anselmo Moriscot, Ubiratan Fabres Machado

Barros RP, Gabbi C, Morani A, Warner M, Gustafsson JA. Participation of ER and ER in glucose home... more Barros RP, Gabbi C, Morani A, Warner M, Gustafsson JA. Participation of ER and ER in glucose homeostasis in skeletal muscle and white adipose tissue. Am J Physiol Endocrinol Metab 297: E124–E133, 2009. First published April 14, 2009; doi:10.1152/ajpendo.00189.2009.—Glucose uptake and homeostasis are regulated mainly by skeletal muscle (SM), white adipose tissue (WAT), pancreas, and the liver. Participation of estradiol in this regulation is still under intense investigation. We have demonstrated that, in SM of male mice, expression of the insulinregulated glucose transporter (GLUT)4 is reduced by estrogen receptor (ER) agonists. In the present study, to investigate the relative contributions of ER and ER in glucose homeostasis, we examined the effects of tamoxifen (Tam) on GLUT4 expression in SM and WAT in wild-type (WT) and ER / mice. ER / mice were characterized by fasting hypoglycemia, increased levels of SM GLUT4, pancreatic islet hypertrophy, and a belated rise in plasma insuli...

Cancer research, 2006

Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediat... more Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediate their effects through two estrogen receptors (ER), namely ERalpha and ERbeta. ERalpha mediates the proliferative effect of estrogen in breast cancer cells, whereas ERbeta seems to be antiproliferative. We engineered ERalpha-positive T47D breast cancer cells to express ERbeta in a Tet-Off-regulated manner. These cells were then injected orthotopically into severe combined immunodeficient mice, and the growth of the resulting tumors was compared with tumors resulting from injecting the parental T47D cells that do not express ERbeta. The presence of ERbeta resulted in a reduction in tumor growth. Comparison of the ERbeta-expressing and non-ERbeta-expressing tumors revealed that the expression of ERbeta caused a reduction in the number of intratumoral blood vessels and a decrease in expression of the proangiogenic factors vascular endothelial growth factor (VEGF) and platelet-derived growt...

In this study, we compared the uterine tissue of estrogen receptor (ER)beta(-/-) mice and their W... more In this study, we compared the uterine tissue of estrogen receptor (ER)beta(-/-) mice and their WT littermates for differences in morphology, proliferation [the percentage of labeled cells 2 h after BrdUrd injection and EGF receptor (EGFR) expression], and differentiation (expression of progesterone receptor, E-cadherin, and cytokeratins). In ovariectomized mice, progesterone receptor expression in the uterine epithelium was similar in WT and ERbeta(-/-) mice, but E-cadherin and cytokeratin 18 expression was lower in ERbeta(-/-) mice. The percentage of cells in S phase was 1.5% in WT mice and 8% in ERbeta(-/-) mice. Sixteen hours after injection of 17beta-estradiol (E(2)), the number of BrdUrd-labeled cells increased 20-fold in WT mice and 80-fold in ERbeta(-/-) mice. Although ERalpha was abundant in intact mice, after ovariectomy, ERalpha could not be detected in the luminal epithelium of either WT or ERbeta(-/-) mice. In both untreated and E(2)-treated mice, ERalpha and ERbeta wer...

Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediat... more Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediate their effects through two estrogen receptors (ER), namely ERA and ERB. ERA mediates the proliferative effect of estrogen in breast cancer cells, whereas ERB seems to be antiproliferative. We engineered ERA-positive T47D breast cancer cells to express ERB in a Tet-Off–regulated manner. These cells were then injected orthotopically into severe combined immunodeficient mice, and the growth of the resulting tumors was compared with tumors resulting from injecting the parental T47D cells that do not express ERB. The presence of ERB resulted in a reduction in tumor growth. Comparison of the ERB-expressing and non-ERB–expressing tumors revealed that the expression of ERB caused a reduction in the number of intratumoral blood vessels and a decrease in expression of the proangiogenic factors vascular endothelial growth factor (VEGF) and platelet-derived growth factor B (PDGFB). In cell culture,...

Identification of spinK3 as indicator of ER beta negative, poorly differentiated prostatic epithe... more Identification of spinK3 as indicator of ER beta negative, poorly differentiated prostatic epithelium by isotope coded protein labeling and LC-ESI-MS/MS. Mol. And Cell. Prot. 2008

Proceedings of the National Academy of Sciences of the United States of America, 2004

Proceedings of the National Academy of Sciences of the United States of America, 2006

Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediat... more Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediate their effects through two estrogen receptors (ER), namely ERA and ERB .E RA mediates the proliferative effect of estrogen in breast cancer cells, whereas ERB seems to be antiproliferative. We engi- neered ERA-positive T47D breast cancer cells to express ERB in a Tet-Off-regulated manner. These

Proceedings of the National Academy of Sciences, 2007

Proceedings of the National Academy of Sciences, 2004

Journal of Internal Medicine, 2008

Proceedings of the …, 2007

Cancer Research, 2006

Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediat... more Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediate their effects through two estrogen receptors (ER), namely ERA and ERB. ERA mediates the proliferative effect of estrogen in breast cancer cells, whereas ERB seems to be antiproliferative. We engineered ERA-positive T47D breast cancer cells to express ERB in a Tet-Off-regulated manner. These cells were then injected orthotopically into severe combined immunodeficient mice, and the growth of the resulting tumors was compared with tumors resulting from injecting the parental T47D cells that do not express ERB. The presence of ERB resulted in a reduction in tumor growth. Comparison of the ERB-expressing and non-ERB-expressing tumors revealed that the expression of ERB caused a reduction in the number of intratumoral blood vessels and a decrease in expression of the proangiogenic factors vascular endothelial growth factor (VEGF) and platelet-derived growth factor B (PDGFB). In cell culture, with the Tet-Off-regulated ERB-expressing cells, expression of ERB decreased expression of VEGF and PDGFB mRNA under normoxic as well as hypoxic conditions and reduced secreted VEGF and PDGFB proteins in cell culture medium. Transient transfection assays with 1,026 bp VEGF and 1,006 bp PDGFB promoter constructs revealed a repressive effect of ERB at the promoter level of these genes. Taken together, these data show that introduction of ERB into malignant cells inhibits their growth and prevents tumor expansion by inhibiting angiogenesis.

Molecular and cellular …, 2008

Proceedings of the …, 2006

In this study, we compared the uterine tissue of estrogen receptor (ER)β −/− mice and their WT li... more In this study, we compared the uterine tissue of estrogen receptor (ER)β −/− mice and their WT littermates for differences in morphology, proliferation [the percentage of labeled cells 2 h after BrdUrd injection and EGF receptor (EGFR) expression], and differentiation (expression of ...

Estrogen receptors (ER) are important regulators of metabolic diseases such as obesity and insuli... more Estrogen receptors (ER) are important regulators of metabolic diseases such as obesity and insulin resistance (IR). While ERa seems to have a protective role in such diseases, the function of ERb is not clear. To characterize the metabolic function of ERb, we investigated its molecular interaction with a master regulator of insulin signaling/glucose metabolism, the PPARc, in vitro and in high-fat diet (HFD)-fed ERb-/- mice (bERKO) mice. Our in vitro experiments showed that ERb inhibits ligandmediated PPARc-transcriptional activity. That resulted in a blockade of PPARc-induced adipocytic gene expression and in decreased adipogenesis. Overexpression of nuclear coactivators such as SRC1 and TIF2 prevented the ERb-mediated inhibition of PPARc activity. Consistent with the in vitro data, we observed increased PPARc activity in gonadal fat from HFD-fed bERKO mice. In consonance with enhanced PPARc activation, HFD-fed bERKO mice showed increased body weight gain and fat mass in the presenc...

Breast cancer is the most common malignancy among Swedish women. Although the mechanism behind th... more Breast cancer is the most common malignancy among Swedish women. Although the mechanism behind the tumorigenesis remains unclear, estrogen receptor α (ERα) plays an important role in the progression of breast cancer and is regarded as a target for endocrine therapy. In this thesis, focus is on the second estrogen receptor, ERβ and its function in breast cancer. In addition, the significance of the transcription factors Hes-1 and Hes-6 in breast cancer and their relation to ERα has been studied. By using T47D breast cancer cells with inducible ERβ expression, the role of ERβ has been characterised with respect to proliferation and cell-cycle regulation. In contrast to ERα, expression of ERβ inhibited the proliferation of 17β-estradiol (E2) treated breast cancer cells and caused significantly changed levels of cell-cycle regulators. In response to ERβ expression, the levels of the Cdk2-activating phosphatase Cdc25A as well as cyclin E and E2F1 were reduced with a subsequent decrease o...

Proceedings of the National Academy of Sciences of the United States of America, 2006

Estrogen receptor beta (ERbeta) is highly expressed in both type I and II pneumocytes as well as ... more Estrogen receptor beta (ERbeta) is highly expressed in both type I and II pneumocytes as well as bronchiolar epithelial cells. ERalpha is not detectable in the adult lung. Lungs of adult female ERbeta knockout (ERbeta-/-) mice have already been reported to have fewer alveoli and reduced elastic recoil. In this article, we report that, by 5 months of age, there are large areas of unexpanded alveoli in lungs of both male and female ERbeta-/- mice. There is increased staining for collagen and, by EM, abnormal clusters of collagen fibers are seen in the alveolar septa of ERbeta-/- mice. Immunohistochemical analysis and Western blotting with lung membrane fractions of ERbeta-/- mice revealed down-regulation of caveolin-1, increased expression of membrane type-1 metalloproteinase, matrix metalloproteinase 2 (active form), and tissue inhibitors of metalloproteinases 2. Hypoxia, measured by immunohistochemical analysis for hypoxia-inducible factor 1alpha and chemical adducts (with Hypoxypro...

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific r... more HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Insulin resistance of pregnancy involves estrogen-induced repression of muscle GLUT4 Rodrigo Palazzo de Almeida Barros, Andrea Morani, Anselmo Moriscot, Ubiratan Fabres Machado

Barros RP, Gabbi C, Morani A, Warner M, Gustafsson JA. Participation of ER and ER in glucose home... more Barros RP, Gabbi C, Morani A, Warner M, Gustafsson JA. Participation of ER and ER in glucose homeostasis in skeletal muscle and white adipose tissue. Am J Physiol Endocrinol Metab 297: E124–E133, 2009. First published April 14, 2009; doi:10.1152/ajpendo.00189.2009.—Glucose uptake and homeostasis are regulated mainly by skeletal muscle (SM), white adipose tissue (WAT), pancreas, and the liver. Participation of estradiol in this regulation is still under intense investigation. We have demonstrated that, in SM of male mice, expression of the insulinregulated glucose transporter (GLUT)4 is reduced by estrogen receptor (ER) agonists. In the present study, to investigate the relative contributions of ER and ER in glucose homeostasis, we examined the effects of tamoxifen (Tam) on GLUT4 expression in SM and WAT in wild-type (WT) and ER / mice. ER / mice were characterized by fasting hypoglycemia, increased levels of SM GLUT4, pancreatic islet hypertrophy, and a belated rise in plasma insuli...

Cancer research, 2006

Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediat... more Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediate their effects through two estrogen receptors (ER), namely ERalpha and ERbeta. ERalpha mediates the proliferative effect of estrogen in breast cancer cells, whereas ERbeta seems to be antiproliferative. We engineered ERalpha-positive T47D breast cancer cells to express ERbeta in a Tet-Off-regulated manner. These cells were then injected orthotopically into severe combined immunodeficient mice, and the growth of the resulting tumors was compared with tumors resulting from injecting the parental T47D cells that do not express ERbeta. The presence of ERbeta resulted in a reduction in tumor growth. Comparison of the ERbeta-expressing and non-ERbeta-expressing tumors revealed that the expression of ERbeta caused a reduction in the number of intratumoral blood vessels and a decrease in expression of the proangiogenic factors vascular endothelial growth factor (VEGF) and platelet-derived growt...

In this study, we compared the uterine tissue of estrogen receptor (ER)beta(-/-) mice and their W... more In this study, we compared the uterine tissue of estrogen receptor (ER)beta(-/-) mice and their WT littermates for differences in morphology, proliferation [the percentage of labeled cells 2 h after BrdUrd injection and EGF receptor (EGFR) expression], and differentiation (expression of progesterone receptor, E-cadherin, and cytokeratins). In ovariectomized mice, progesterone receptor expression in the uterine epithelium was similar in WT and ERbeta(-/-) mice, but E-cadherin and cytokeratin 18 expression was lower in ERbeta(-/-) mice. The percentage of cells in S phase was 1.5% in WT mice and 8% in ERbeta(-/-) mice. Sixteen hours after injection of 17beta-estradiol (E(2)), the number of BrdUrd-labeled cells increased 20-fold in WT mice and 80-fold in ERbeta(-/-) mice. Although ERalpha was abundant in intact mice, after ovariectomy, ERalpha could not be detected in the luminal epithelium of either WT or ERbeta(-/-) mice. In both untreated and E(2)-treated mice, ERalpha and ERbeta wer...

Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediat... more Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediate their effects through two estrogen receptors (ER), namely ERA and ERB. ERA mediates the proliferative effect of estrogen in breast cancer cells, whereas ERB seems to be antiproliferative. We engineered ERA-positive T47D breast cancer cells to express ERB in a Tet-Off–regulated manner. These cells were then injected orthotopically into severe combined immunodeficient mice, and the growth of the resulting tumors was compared with tumors resulting from injecting the parental T47D cells that do not express ERB. The presence of ERB resulted in a reduction in tumor growth. Comparison of the ERB-expressing and non-ERB–expressing tumors revealed that the expression of ERB caused a reduction in the number of intratumoral blood vessels and a decrease in expression of the proangiogenic factors vascular endothelial growth factor (VEGF) and platelet-derived growth factor B (PDGFB). In cell culture,...

Identification of spinK3 as indicator of ER beta negative, poorly differentiated prostatic epithe... more Identification of spinK3 as indicator of ER beta negative, poorly differentiated prostatic epithelium by isotope coded protein labeling and LC-ESI-MS/MS. Mol. And Cell. Prot. 2008

Proceedings of the National Academy of Sciences of the United States of America, 2004

Proceedings of the National Academy of Sciences of the United States of America, 2006

Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediat... more Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediate their effects through two estrogen receptors (ER), namely ERA and ERB .E RA mediates the proliferative effect of estrogen in breast cancer cells, whereas ERB seems to be antiproliferative. We engi- neered ERA-positive T47D breast cancer cells to express ERB in a Tet-Off-regulated manner. These

Proceedings of the National Academy of Sciences, 2007

Proceedings of the National Academy of Sciences, 2004

Journal of Internal Medicine, 2008

Proceedings of the …, 2007

Cancer Research, 2006

Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediat... more Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediate their effects through two estrogen receptors (ER), namely ERA and ERB. ERA mediates the proliferative effect of estrogen in breast cancer cells, whereas ERB seems to be antiproliferative. We engineered ERA-positive T47D breast cancer cells to express ERB in a Tet-Off-regulated manner. These cells were then injected orthotopically into severe combined immunodeficient mice, and the growth of the resulting tumors was compared with tumors resulting from injecting the parental T47D cells that do not express ERB. The presence of ERB resulted in a reduction in tumor growth. Comparison of the ERB-expressing and non-ERB-expressing tumors revealed that the expression of ERB caused a reduction in the number of intratumoral blood vessels and a decrease in expression of the proangiogenic factors vascular endothelial growth factor (VEGF) and platelet-derived growth factor B (PDGFB). In cell culture, with the Tet-Off-regulated ERB-expressing cells, expression of ERB decreased expression of VEGF and PDGFB mRNA under normoxic as well as hypoxic conditions and reduced secreted VEGF and PDGFB proteins in cell culture medium. Transient transfection assays with 1,026 bp VEGF and 1,006 bp PDGFB promoter constructs revealed a repressive effect of ERB at the promoter level of these genes. Taken together, these data show that introduction of ERB into malignant cells inhibits their growth and prevents tumor expansion by inhibiting angiogenesis.

Molecular and cellular …, 2008

Proceedings of the …, 2006

In this study, we compared the uterine tissue of estrogen receptor (ER)β −/− mice and their WT li... more In this study, we compared the uterine tissue of estrogen receptor (ER)β −/− mice and their WT littermates for differences in morphology, proliferation [the percentage of labeled cells 2 h after BrdUrd injection and EGF receptor (EGFR) expression], and differentiation (expression of ...