RESUMO
Gaze-evoked amaurosis is a transient monocular vision loss elicited by eccentric gaze and has been reported in many orbital conditions but is most classically associated with intraconal tumors, such as cavernous hemangioma and optic nerve sheath meningioma. Here, the authors report a case of gaze-evoked amaurosis due to idiopathic orbital inflammation. The patient was a 35-year-old man who presented with vision loss only when abducting his left eye. He had a history of sclerosing idiopathic orbital inflammation with a left orbital intraconal mass diagnosed 15 months prior to the current presentation. The patient had difficulty with immunosuppressive therapy, which was stopped 5 months prior to presentation. Repeat imaging during the current presentation revealed enlargement of the mass. This case demonstrates that idiopathic orbital inflammation should be considered in the differential diagnosis for gaze-evoked amaurosis, which may be the first symptom of disease progression.
Assuntos
Hemangioma Cavernoso , Neoplasias Meníngeas , Neoplasias Orbitárias , Pseudotumor Orbitário , Adulto , Cegueira , Hemangioma Cavernoso/patologia , Humanos , Inflamação/complicações , Masculino , Neoplasias Orbitárias/patologia , Pseudotumor Orbitário/complicaçõesRESUMO
Glutamine synthetase (GS) is the enzyme responsible for the biosynthesis of glutamine, providing the only source of endogenous glutamine necessary for several critical metabolic and developmental pathways. GS deficiency, caused by pathogenic variants in the glutamate-ammonia ligase (GLUL) gene, is a rare autosomal recessive inborn error of metabolism characterized by systemic glutamine deficiency, persistent moderate hyperammonemia, and clinically devastating seizures and multi-organ failure shortly after birth. The four cases reported thus far were caused by homozygous GLUL missense variants. We report a case of GS deficiency caused by homozygous GLUL gene deletion, diagnosed prenatally and likely representing the most severe end of the spectrum. We expand the known phenotype of this rare condition with novel dysmorphic, radiographic and neuropathologic features identified on post-mortem examination. The biallelic deletion identified in this case also included the RNASEL gene and was associated with immune dysfunction in the fetus. This case demonstrates that total absence of the GLUL gene in humans is viable beyond the embryonic period, despite the early embryonic lethality found in GLUL animal models.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Glutamato-Amônia Ligase/deficiência , Glutamato-Amônia Ligase/genética , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Feminino , Feto , Glutamina/genética , Homozigoto , Humanos , Recém-Nascido , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/patologiaRESUMO
Background: Gender affirming surgeries are increasingly accessible to transgender and non-binary individuals due to changes in health care coverage policies and rising numbers of trained providers. Improved access to care has led to an increase in the number of individuals pursuing gender affirming surgeries. Little is known about how to optimally prepare patients for these surgeries. Aims: This evaluation examined attendees' assessment of a four-hour single-session class developed to prepare transgender and non-binary patients and their caregivers for gender affirming surgeries in a multi-disciplinary transgender clinic within an integrated health care system. Methods: A multi-disciplinary group of providers within a health maintenance organization in Northern California designed and facilitated two separate curricula, one for patients preparing for metoidioplasty/phalloplasty and the other preparing for vaginoplasty. Between November 2015 and June 2017, 214 patients and caregivers took one of the two versions of the class and completed the post-class survey evaluating perceived favorability of the class and preparedness regarding surgery options, complications and postoperative care. Descriptive statistics were used to summarize the Likert scale questions, with 1 showing the least improvement and 5 showing the most. Results: Of the 214 patients and caregivers that completed the survey, the majority reported that they were better informed about their surgical options (mean: 4.4, SD: 0.7), more prepared for surgery (mean: 4.5, SD: 0.6), better informed about possible complications (mean: 4.5, SD: 0.7), and better understood their postoperative care needs (mean: 4.6, SD: 0.6). Of the respondents, 204 (95%) reported they would recommend the course to a friend preparing for gender affirming surgery. Discussion: Our findings demonstrate that a single-session class is a favorable method for preparing transgender and non-binary patients to make informed decisions regarding the perioperative gender affirming surgical process, from preoperative preparedness, to surgical complications, and postoperative care.
RESUMO
Bone metastases are a frequent complication of many cancers that result in severe disease burden and pain. Since the late nineteenth century, it has been thought that the microenvironment of the local host tissue actively participates in the propensity of certain cancers to metastasize to specific organs, and that bone provides an especially fertile 'soil'. In the case of breast cancers, the local chemokine milieu is now emerging as an explanation for why these tumours preferentially metastasize to certain organs. However, as the inhibition of chemokine receptors in vivo only partially blocks metastatic behaviour, other factors must exist that regulate the preferential metastasis of breast cancer cells. Here we show that the cytokine RANKL (receptor activator of NF-kappaB ligand) triggers migration of human epithelial cancer cells and melanoma cells that express the receptor RANK. RANK is expressed on cancer cell lines and breast cancer cells in patients. In a mouse model of melanoma metastasis, in vivo neutralization of RANKL by osteoprotegerin results in complete protection from paralysis and a marked reduction in tumour burden in bones but not in other organs. Our data show that local differentiation factors such as RANKL have an important role in cell migration and the tissue-specific metastatic behaviour of cancer cells.
Assuntos
Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Proteínas de Transporte/metabolismo , Movimento Celular , Glicoproteínas de Membrana/metabolismo , Metástase Neoplásica/patologia , Animais , Neoplasias Ósseas/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Transporte/genética , Morte Celular , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Células Epiteliais/patologia , Feminino , Humanos , Melanoma/metabolismo , Melanoma/patologia , Glicoproteínas de Membrana/genética , Camundongos , Especificidade de Órgãos , Paralisia , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Transdução de SinaisRESUMO
Despite global digitization, evaluating pathology trainees by paper exams remains the norm. As new social distancing practices require new ways of administering exams, we assessed the viability of an online format for in-house exams from the resident and examiner perspectives. First, pathology residents participated in a practice exam, while staff who were experienced in creating exams were given an online exam-creation demonstration. Subsequently, residents completed a formal 3-hour online exam comprised of multiple-choice, matching, short answer, and whole slide images in place of the paper exam regularly used to evaluate trainees. The experience of the participants was evaluated by surveys. Eighteen residents completed the practice exam; 67% were receptive to the new format and 94% were in favor of moving to digital exams. Seven staff evaluated the digital format and 6 were in favor of it. For the formal online in-house exam, 20 residents participated and 14 completed the survey. Feedback was generally positive with the most common issue being slow-loading digital slides. Exam scores stratified by postgraduate training years in a statistically significant manner, showing positive correlation with resident training level. The online exam format was preferred over paper exams by trainees, with support from both staff and trainees for a permanent transition. Online exams have clear advantages, but technical issues should be addressed before widespread implementation. Our study demonstrates that online exams are a feasible alternative for trainee assessment, especially in socially distanced environments.
RESUMO
Extracellular matrix (ECM) fragments or cryptic sites unmasked by proteinases have been postulated to affect tissue remodeling and cancer progression. Therefore, the elucidation of their identities and functions is of great interest. Here, we show that matrix metalloproteinases (MMPs) generate a domain (DIII) from the ECM macromolecule laminin-5. Binding of a recombinant DIII fragment to epidermal growth factor receptor stimulates downstream signaling (mitogen-activated protein kinase), MMP-2 gene expression, and cell migration. Appearance of this cryptic ECM ligand in remodeling mammary gland coincides with MMP-mediated involution in wild-type mice, but not in tissue inhibitor of metalloproteinase 3 (TIMP-3)-deficient mice, supporting physiological regulation of DIII liberation. These findings indicate that ECM cues may operate via direct stimulation of receptor tyrosine kinases in tissue remodeling, and possibly cancer invasion.
Assuntos
Mama/enzimologia , Moléculas de Adesão Celular/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Células Epiteliais/enzimologia , Receptores ErbB/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Metaloproteinases da Matriz/metabolismo , Animais , Membrana Basal/metabolismo , Mama/citologia , Mama/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Movimento Celular/genética , Células Cultivadas , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Proteínas da Matriz Extracelular/genética , Feminino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Invasividade Neoplásica/genética , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/genética , Estrutura Terciária de Proteína/genética , Receptores Proteína Tirosina Quinases/metabolismo , Inibidor Tecidual de Metaloproteinase-3/deficiência , Inibidor Tecidual de Metaloproteinase-3/genética , CalininaRESUMO
Two rapidly evolving fields are converging to impact breast cancer: one has identified novel substrates of metalloproteinases that alter immune cell function, and the other has revealed a role for inflammation in human cancers. Evidence now shows that the mechanisms underlying these two fields interact in the context of breast cancer, providing new opportunities to understand this disease and uncover novel therapeutic strategies. The metalloproteinase class of enzymes is well studied in mammary gland development and physiology, but mostly in the context of extracellular matrix modification. Aberrant metalloproteinase expression has also been implicated in breast cancer progression, where these genes act as tumor modifiers. Here, we review how the metalloproteinase axis impacts mammary physiology and tumorigenesis and is associated with inflammatory cell influx in human breast cancer, and evaluate its potential as a regulator of inflammation in the mammary gland.
Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Matriz Extracelular/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/enzimologia , Metaloproteases/metabolismo , Proteínas ADAM/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/imunologia , Matriz Extracelular/enzimologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Inflamação/metabolismo , Linfócitos , Camundongos , Inibidores Teciduais de Metaloproteinases/metabolismoRESUMO
Cbl family proteins are evolutionarily conserved ubiquitin ligases that negatively regulate signaling from tyrosine kinase-coupled receptors. The mammalian cbl family consists of c-Cbl, Cbl-b, and the recently cloned Cbl-3 (also known as Cbl-c). In this study, we describe the detailed expression pattern of murine Cbl-3 and report the generation and characterization of Cbl-3-deficient mice. Cbl-3 exhibits an expression pattern distinct from those of c-Cbl and Cbl-b, with high levels of Cbl-3 expression in epithelial cells of the gastrointestinal tract and epidermis, as well as the respiratory, urinary, and reproductive systems. Cbl-3 expression was not detected in nonepithelial cells, but within epithelial tissues, the levels of Cbl-3 expression varied from undetectable in the alveoli of the lungs to very strong in the cecum and colon. Despite this restricted expression pattern, Cbl-3-deficient mice were viable, healthy, and fertile and displayed no histological abnormalities up to 18 months of age. Proliferation of epithelial cells in the epidermises and gastrointestinal tracts was unaffected by the loss of Cbl-3. Moreover, Cbl-3 was not required for attenuation of epidermal growth factor-stimulated Erk activation in primary keratinocytes. Thus, Cbl-3 is dispensable for normal epithelial development and function.
Assuntos
Células Epiteliais/metabolismo , Epitélio/crescimento & desenvolvimento , Proteínas Oncogênicas de Retroviridae/metabolismo , Animais , Células Cultivadas , Ativação Enzimática , Células Epiteliais/citologia , Epitélio/anatomia & histologia , Regulação da Expressão Gênica , Marcação de Genes , Humanos , Hibridização In Situ , Queratinócitos/citologia , Queratinócitos/metabolismo , Camundongos , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-cbl , Proteínas Oncogênicas de Retroviridae/genética , Distribuição TecidualRESUMO
BACKGROUND: Despite the mounting clinical burden of heart failure, the biomolecules that control myocardial tissue remodeling are poorly understood. TIMP-3 is an endogenous inhibitor of matrix metalloproteinases (MMPs) that has been found to be deficient in failing human myocardium. We hypothesized that TIMP-3 expression prevents maladaptive tissue remodeling in the heart, and accordingly, its deficiency in mice would alone be sufficient to trigger progressive cardiac remodeling and dysfunction similar to human heart failure. METHODS AND RESULTS: Mice with a targeted timp-3 deficiency were evaluated with aging and compared with age-matched wild-type littermates. Loss of timp-3 function triggered spontaneous LV dilatation, cardiomyocyte hypertrophy, and contractile dysfunction at 21 months of age consistent with human dilated cardiomyopathy. Its absence also resulted in interstitial matrix disruption with elevated MMP-9 activity, and activation of the proinflammatory tumor necrosis factor-alpha cytokine system, molecular hallmarks of human myocardial remodeling. CONCLUSIONS: TIMP-3 deficiency disrupts matrix homeostasis and the balance of inflammatory mediators, eliciting the transition to cardiac dilation and dysfunction. Therapeutic restoration of myocardial TIMP-3 may provide a novel approach to limit cardiac remodeling and the progression to failure in patients with dilated cardiomyopathy.
Assuntos
Cardiomiopatia Dilatada/enzimologia , Inibidor Tecidual de Metaloproteinase-3/deficiência , Proteínas ADAM , Proteína ADAM17 , Animais , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/patologia , Colágeno/análise , Progressão da Doença , Matriz Extracelular/química , Homeostase , Hipertrofia , Macrófagos/patologia , Metaloproteinase 9 da Matriz/análise , Metaloendopeptidases/análise , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Cardiovasculares , Contração Miocárdica , Miócitos Cardíacos/patologia , Nitritos/análise , Receptores Tipo II do Fator de Necrose Tumoral/análise , Inibidor Tecidual de Metaloproteinase-3/genética , Inibidor Tecidual de Metaloproteinase-3/fisiologia , Fator de Necrose Tumoral alfa/análise , UltrassonografiaRESUMO
Timp3 is commonly silenced in breast cancer, but mechanistic studies have identified both tumor promotion and suppression effects of this gene. We have taken a genetic approach to determine the impact of Timp3 loss on two mouse models of breast cancer. Interestingly, MMTV-PyMT Timp3-/- mice have delayed tumor onset and 36% of MMTV-Neu Timp3-/- mice remain tumor free. TIMP3 is a regulator of TNF signaling and similar to Timp3, Tnf or Tnfr1 loss delays early tumorigenesis. The tumor suppression in Timp3 null mice requires Tnfr1, but does not result in alterations in the local immune compartment. In the mammary gland, Timps are highly expressed in the stroma and through the transplantation of tumor cells we observe that Timp3 deficiency in the host is sufficient to delay the growth of early, but not advanced tumor cells. Together our data is the first to identify a tumor promoting role of endogenous Timp3 in vivo, the spatial and temporal windows of this effect, and its dependence on Tnfr1.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/genética , Inibidor Tecidual de Metaloproteinase-3/deficiência , Inibidor Tecidual de Metaloproteinase-3/genética , Animais , Transformação Celular Neoplásica/patologia , Feminino , Masculino , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
To test if proteolysis is involved in tumor cell extravasation, we developed an in vitro model where tumor cells cross an endothelial monolayer cultured on a basement membrane. Using this model we classified the ability of the cells to transmigrate through the endothelial cell barrier onto the underlying matrix, and scored this invasion according to the stage of passage through the endothelium. Metalloproteinase inhibitors reduced tumor cell extravasation by at least 35%. Visualization of protease and cell adhesion molecules by confocal microscopy demonstrated the cell surface localization of MMP-2, MMP-9, MT1-MMP, furin, CD44 and αvß3, during the process of transendothelial migration. By the addition of inhibitors and bio-modulators we assessed the functional requirement of the aforementioned molecules for efficient migration. Proteolytic digestion occurred at the cell-matrix interface and was most evident during the migratory stage. All of the inhibitors and biomodulators affected the transition of the tumor cells into the migratory stage, highlighting the most prevalent use of proteolysis at this particular step of tumor cell extravasation. These data suggest that a proteolytic interface operates at the tumor cell surface within the tumor-endothelial cell microenvironment.
Assuntos
Metaloproteases/metabolismo , Proteólise , Migração Transendotelial e Transepitelial/fisiologia , Células Tumorais Cultivadas/fisiologia , Microambiente Tumoral/fisiologia , Western Blotting , Moléculas de Adesão Celular/metabolismo , Imunofluorescência , Humanos , Técnicas In Vitro , Metaloproteases/antagonistas & inibidores , Microscopia ConfocalRESUMO
Post-lactation mammary involution is a homeostatic process requiring epithelial apoptosis and clearance. Given that the deficiency of the extracellular metalloproteinase inhibitor TIMP3 impacts epithelial apoptosis and heightens inflammatory response, we investigated whether TIMP3 regulates these distinct processes during the phases of mammary gland involution in the mouse. Here we show that TIMP3 deficiency leads to TNF dysregulation, earlier caspase activation and onset of mitochondrial apoptosis. This accelerated first phase of involution includes faster loss of initiating signals (STAT3 activation; TGFß3) concurrent with immediate luminal deconstruction through E-cadherin fragmentation. Epithelial apoptosis is followed by accelerated adipogenesis and a greater macrophage and T-cell infiltration in Timp3(-/-) involuting glands. Crossing in Tnf deficiency abrogates caspase 3 activation, but heightens macrophage and T-cell influx into Timp3(-/-) glands. The data indicate that TIMP3 differentially impacts apoptosis and inflammatory cell influx, based on involvement of TNF, during the process of mammary involution. An understanding of the molecular factors and wound healing microenvironment of the postpartum mammary gland may have implications for understanding pregnancy-associated breast cancer risk.
Assuntos
Apoptose , Células Epiteliais/imunologia , Células Epiteliais/patologia , Linfócitos/imunologia , Glândulas Mamárias Animais/patologia , Inibidor Tecidual de Metaloproteinase-3/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Junções Aderentes/efeitos dos fármacos , Junções Aderentes/metabolismo , Adipogenia/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Caderinas/metabolismo , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Feminino , Humanos , Inflamação/patologia , Linfócitos/efeitos dos fármacos , Glândulas Mamárias Animais/enzimologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-3/deficiênciaRESUMO
Transforming growth factor beta (TGF-beta) is a crucial mediator of breast development, and loss of TGF-beta-induced growth arrest is a hallmark of breast cancer. TGF-beta has been shown to inhibit cyclin-dependent kinase (CDK) activity, which leads to the accumulation of hypophosphorylated pRB. However, unlike other components of TGF-beta cytostatic signaling, pRB is thought to be dispensable for mammary development. Using gene-targeted mice carrying subtle missense changes in pRB (Rb1(DeltaL) and Rb1(NF)), we have discovered that pRB plays a critical role in mammary gland development. In particular, Rb1 mutant female mice have hyperplastic mammary epithelium and defects in nursing due to insensitivity to TGF-beta growth inhibition. In contrast with previous studies that highlighted the inhibition of cyclin/CDK activity by TGF-beta signaling, our experiments revealed that active transcriptional repression of E2F target genes by pRB downstream of CDKs is also a key component of TGF-beta cytostatic signaling. Taken together, our work demonstrates a unique functional connection between pRB and TGF-beta in growth control and mammary gland development.
Assuntos
Glândulas Mamárias Animais/crescimento & desenvolvimento , Proteína do Retinoblastoma/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Células Cultivadas , Feminino , Técnicas de Introdução de Genes , Genótipo , Humanos , Hiperplasia/metabolismo , Hiperplasia/patologia , Lactação , Masculino , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Moleculares , Fenótipo , Conformação Proteica , Proteína do Retinoblastoma/genética , Transdução de Sinais/fisiologia , Transplante de Tecidos , Fator de Crescimento Transformador beta/genéticaRESUMO
Multiple cancers exhibit mutations in beta-catenin that lead to increased stability, altered localization or amplified activity. beta-catenin is situated at the junction between the cadherin-mediated cell adhesion and Wnt signaling pathways, and TIMP3 functions to alter beta-catenin signaling. Here we demonstrate that primary mouse embryonic fibroblasts (MEFs) and mammary epithelial cells (MECs) deficient in Timp3 have increased beta-catenin signaling. Functionally, the loss of TIMP3 exerted cell-type-specific effects, with Timp3(-/-) MEFs being more sensitive and Timp3(-/-) MECs more resistant to EGTA-induced cell detachment than the wild type. Timp3(-/-) MECs had higher dephosphorylated beta-catenin levels and increased beta-catenin transcriptional activity as measured by TCF/LEF-responsive reporter assays. Real-time PCR analysis of beta-catenin target genes in MEFs and MECs showed no alteration in Myc, decreased Ccnd1 (cyclin D1) and increased Mmp7 mRNA levels upon loss of TIMP3, with the latter occurring only in epithelial cells. Recombinant TIMP3 and synthetic metalloproteinase inhibitors reverted the increase in dephosphorylated beta-catenin, decrease in Ccnd1 gene expression and increase in Mmp7 gene expression. Physiologically, Timp3(-/-) mammary glands displayed accelerated mammary ductal elongation during pubertal morphogenesis. Gain-of-function studies using slow-release TIMP-containing pellets revealed distinct effects of individual TIMPs on ductal morphogenesis. Recombinant TIMP1, TIMP3 and TIMP4 inhibited ductal elongation whereas TIMP2 promoted this process.
Assuntos
Células Epiteliais/fisiologia , Glândulas Mamárias Animais/fisiologia , Metaloproteinase 7 da Matriz/metabolismo , Transdução de Sinais , Inibidor Tecidual de Metaloproteinase-3/fisiologia , beta Catenina/fisiologia , Animais , Adesão Celular/fisiologia , Células Cultivadas , Ciclina D , Ciclinas/metabolismo , Ácido Egtázico/química , Estruturas Embrionárias/citologia , Feminino , Fibroblastos/fisiologia , Genes myc/fisiologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Camundongos , Camundongos Knockout , Fosforilação , Proteínas Recombinantes/metabolismo , Inibidor Tecidual de Metaloproteinase-3/genética , Ativação Transcricional/fisiologiaRESUMO
The tumor suppressor PTEN is altered in many cancers, including breast cancer, but only a handful of factors are known to control its expression. PTEN plays a vital role in cell survival and proliferation by regulating Akt phosphorylation, a key component of the phosphatidylinositol 3 kinase (PI3K) pathway. Here we show that insulin-like growth factor-II (IGF-II), which signals through PI3K, regulates PTEN expression in the mammary gland. IGF-II injection into mouse mammary gland significantly increased PTEN expression. Transgenic IGF-II expression also increased mammary PTEN protein, leading to reductions in Akt phosphorylation, epithelial proliferation, and mammary morphogenesis. IGF-II induced PTEN promoter activity and protein levels and this involved the immediate early gene egr-1. Thus, we have identified a novel negative feedback loop within the PI3K pathway where IGF-II induces PTEN expression to modulate its physiologic effects.