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1.
Res Sq ; 2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-38978600

RESUMEN

Breastfeeding protects against breast cancer in some women but not others, however the mechanism remains elusive. Lactation requires intense secretory activity of the endoplasmic reticulum (ER) for the production of milk proteins and ER-mitochondria contacts for lipid synthesis. We show that in female mice that share the same nuclear genome (BL/6) but differ in mitochondrial genomes (C57 or NZB), the biological processes engaged during lactation are entirely different at the sub-cellular organization and transcriptional levels resulting in anti-tumorigenic lactation in BL/6C57 females and pro-tumorigenic lactation in BL/6NZB females. Single cell sequencing identified a sub-population of cells, uniquely amplified during lactation in BL/6NZB females, which shares the genetic signature that characterizes post-partum breast cancer (PPBC) in humans relative to matched breast cancers in never pregnant women. Our data indicate that differences in ER and mitochondrial-stress responses during lactation between genotypes inadvertently leads to loss of p53 tumor suppressor function in BL/6NZB females allowing the expansion of the PPBC-like sub-population of cells. Overall, our data reveals the unexpected idiosyncratic nature of lactation and its impacts on the risk of the development of PPBC.

2.
Aging Cell ; 21(10): e13665, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36111352

RESUMEN

A major limitation in the use of mouse models in breast cancer research is that most mice develop estrogen receptor-alpha (ERα)-negative mammary tumors, while in humans, the majority of breast cancers are ERα-positive. Therefore, developing mouse models that best mimic the disease in humans is of fundamental need. Here, using an inducible MMTV-rtTA/TetO-NeuNT mouse model, we show that despite being driven by the same oncogene, mammary tumors in young mice are ERα-negative, while they are ERα-positive in aged mice. To further elucidate the mechanisms for this observation, we performed RNAseq analysis and identified genes that are uniquely expressed in aged female-derived mammary tumors. We found these genes to be involved in the activation of the ERα axis of the mitochondrial UPR and the ERα-mediated regulation of XBP-1s, a gene involved in the endoplasmic reticulum UPR. Collectively, our results indicate that aging alters the oncogenic trajectory towards the ERα-positive subtype of breast cancers, and that mammary tumors in aged mice are characterized by the upregulation of multiple UPR stress responses regulated by the ERα.


Asunto(s)
Receptor alfa de Estrógeno , Receptores de Estrógenos , Anciano , Animales , Carcinogénesis/genética , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Ratones , Oncogenes , Receptores de Estrógenos/metabolismo , Respuesta de Proteína Desplegada/genética
3.
Cell Rep ; 38(3): 110254, 2022 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-35045282

RESUMEN

Cancer heterogeneity and evolution are not fully understood. Here, we show that mitochondrial DNA of the normal liver shapes tumor progression, histology, and immune environment prior to the acquisition of oncogenic mutation. Using conplastic mice, we show that mtDNA dictates the expression of the mitochondrial unfolded protein response (UPRmt) in the normal liver. Activation of oncogenic mutations in UPRmt-positive liver increases tumor incidence and histological heterogeneity. Further, in a subset of UPRmt-positive mice, invasive liver cancers develop. RNA sequencing (RNA-seq) analysis of the normal liver reveals that, in this subset, the PAPP-A/DDR2/SNAIL axis of invasion pre-exists along with elevated collagen. Since PAPP-A promotes immune evasion, we analyzed the immune signature and found that their livers are immunosuppressed. Further, the PAPP-A signature identifies the immune exhausted subset of hepatocellular carcinoma (HCC) in humans. Our data suggest that mtDNA of normal liver shapes the entire liver cancer portrait upon acquisition of oncogenic mutations.


Asunto(s)
Carcinoma Hepatocelular/genética , ADN Mitocondrial/genética , Neoplasias Hepáticas/genética , Respuesta de Proteína Desplegada/genética , Animales , Carcinoma Hepatocelular/patología , Femenino , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína Plasmática A Asociada al Embarazo/metabolismo , Transcriptoma
4.
Aging Cancer ; 2(3): 75-81, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34927079

RESUMEN

Aging is a major risk factor of developing breast cancer. Despite the fact that post-menopausal women have lower levels of estrogen, older women have a higher rate of estrogen receptor alpha (ERα) positive breast cancer. Conversely, young women who have elevated levels of estrogen tend to develop ERα negative disease that is associated with higher rate of metastasis. This perspective proposes a unifying model centered around the importance of mitochondrial biology in cancer and aging to explain these observations. Mitochondria are essential for the survival of cancer cells and therefore pathways that maintain the functionality of the mitochondrial network in cancer cells fulfill a critical role in the survival of cancer cells. The ERα and the mitochondrial sirtuin-3 (SIRT3) have been reported to be key players of the mitochondrial unfolded protein response (UPRmt) 1-5. The UPRmt is a complex retrograde signaling cascade that regulates the communication between the mitochondria and the nucleus to restore mitochondrial fitness in response to oxidative stress 5-7. SIRT3 is a major regulator of aging 8. Its level decreases with age and single nucleotide polymorphisms (SNPs) that preserve its expression at higher levels are observed in centenarians 9,10. We propose a model whereby the ERα axis of the UPRmt acts to compensate for the loss of SIRT3 observed with age, and becomes the dominant axis of the UPRmt to maintain the integrity of the mitochondria during transformation, thus explaining the selective advantage of ERα positive luminal cells in breast cancer arising from older women.

5.
Front Cell Dev Biol ; 9: 715923, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34631705

RESUMEN

Several studies reported that mitochondrial stress induces cytosolic proteostasis. How mitochondrial stress activates proteostasis in the cytosol remains unclear. However, the cross-talk between the mitochondria and cytosolic proteostasis has far reaching implications for treatment of proteopathies including neurodegenerative diseases. This possibility appears within reach since selected drugs have begun to emerge as being able to stimulate mitochondrial-mediated cytosolic proteostasis. In this review, we focus on studies describing how mitochondrial stress activates proteostasis in the cytosol across multiple model organisms. A model is proposed linking mitochondrial-mediated regulation of cytosolic translation, folding capacity, ubiquitination, and proteasome degradation and autophagy as a multi layered control of cytosolic proteostasis that overlaps with the integrated stress response (ISR) and the mitochondrial unfolded protein response (UPRmt). By analogy to the conductor in an orchestra managing multiple instrumental sections into a dynamically integrated musical piece, the cross-talk between these signaling cascades places the mitochondria as a major conductor of cellular integrity.

6.
Sci Rep ; 11(1): 17003, 2021 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-34417525

RESUMEN

Several studies reported that mitochondrial stress induces cytosolic proteostasis in yeast and C. elegans. Notably, inhibition of mitochondrial translation with doxcycyline decreases the toxicity of ß-amyloid aggregates, in a C. elegans. However, how mitochondrial stress activates cytosolic proteostasis remains unclear. Further whether doxycycline has this effect in mammals and in disease relevant tissues also remains unclear. We show here that doxycycline treatment in mice drastically reduces the accumulation of proteins destined for degradation by the proteasome in a CNS region-specific manner. This effect is associated with the activation of the ERα axis of the mitochondrial unfolded protein response (UPRmt), in both males and females. However, sexually dimorphic mechanisms of proteasome activation were observed. Doxycycline also activates the proteasome in fission yeast, where ERα is not expressed. Rather, the ancient ERα-coactivator Mms19 regulates this response in yeast. Our results suggest that the UPRmt initiates a conserved mitochondria-to-cytosol stress signal, resulting in proteasome activation, and that this signal has adapted during evolution, in a sex and tissue specific-manner. Therefore, while our results support the use of doxycycline in the prevention of proteopathic diseases, they also indicate that sex is an important variable to consider in the design of future clinical trials using doxycycline.


Asunto(s)
Sistema Nervioso Central/metabolismo , Doxiciclina/farmacología , Complejo de la Endopetidasa Proteasomal/metabolismo , Animales , Sistema Nervioso Central/efectos de los fármacos , AMP Cíclico/metabolismo , Receptor alfa de Estrógeno/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Complejo de la Endopetidasa Proteasomal/genética , Saccharomyces cerevisiae/metabolismo , Transcripción Genética/efectos de los fármacos , Respuesta de Proteína Desplegada/efectos de los fármacos
7.
Endocrinology ; 162(2)2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33269387

RESUMEN

Several neurodegenerative disorders are characterized by proteasome dysfunctions leading to protein aggregations and pathogenesis. Since we showed that estrogen receptor alpha (ERα) activates the proteasome, drugs able to stimulate ERα in the central nervous system (CNS) could hold potential for therapeutic intervention. However, the transcriptional effects of selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, can be tissue specific. A direct comparison of the effects of different SERMs on gene transcription in the CNS has never been performed. Here, we report an RNA-seq analysis of the spinal cord treated with estrogen, tamoxifen, or raloxifene. We find stark SERM and sex-specific differences in gene expression profiles in the spinal cord. Notably, raloxifene, but not estrogen or tamoxifen, modulates numerous deubiquitinating enzymes, proteasome subunits and assembly factors, and these effects translate into decreased protein aggregates. In the SOD1-G93A mouse model of amyotrophic lateral sclerosis, we found that even a low dose of raloxifene causes a significant decrease in mutant SOD1 aggregates in the spinal cord, accompanied by a delay in the decline of muscle strength in females, but not in males. These results strongly indicate SERM-selective as well as sex-specific effects, and emphasize the importance of sex as a biological variable to be considered for the careful selection of specific SERM for use in clinical trials for neurodegenerative diseases.


Asunto(s)
Enfermedades Neurodegenerativas/tratamiento farmacológico , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Clorhidrato de Raloxifeno/uso terapéutico , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Médula Espinal/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Masculino , Ratones , Complejo de la Endopetidasa Proteasomal/metabolismo , Clorhidrato de Raloxifeno/farmacología , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Caracteres Sexuales , Médula Espinal/enzimología , Ubiquitinación/efectos de los fármacos
8.
J Mammary Gland Biol Neoplasia ; 25(3): 181-189, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32901383

RESUMEN

Insulin-like growth factor (IGF) signaling and control of local bioavailability of free IGF by the IGF binding proteins (IGFBP) are important regulators of both mammary development and breast cancer. A recent genome-wide association study (GWAS) identified small nucleotide polymorphisms that reduce the expression of IGFBP-5 as a risk factor of developing breast cancer. This observation suggests that genetic alterations leading to a decreased level of IGFBP-5 may also contribute to breast cancer. In the current review, we focus on Pregnancy-Associated Plasma Protein A (PAPP-A), a protease involved in the degradation of IGFBP-5. PAPP-A is overexpressed in the majority of breast cancers but its role in cancer has only begun to be explored. More specifically, this review aims at highlighting the role of post-partum involution in the oncogenic function of PAPP-A. Notably, we summarize recent studies indicating that PAPP-A plays a role not only in the degradation of IGFBP-5 but also in the deposition of collagen and activation of the collagen receptor discoidin 2 (DDR2) during post-partum involution. Finally, considering the immunosuppressive microenvironment of post-partum involution, we also discuss the unexpected finding made in Ewing Sarcoma that PAPP-A plays a role in immune evasion. While the immunosuppressive role of PAPP-A in breast cancer remains to be determined, collectively these studies highlight the multifaced role of PAPP-A in cancer that extends well beyond its effect on IGF-signaling.


Asunto(s)
Neoplasias de la Mama/genética , Mama/patología , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Periodo Posparto/genética , Proteína Plasmática A Asociada al Embarazo/genética , Animales , Mama/fisiopatología , Neoplasias de la Mama/patología , Neoplasias de la Mama/fisiopatología , Receptor con Dominio Discoidina 2/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Glándulas Mamarias Animales/patología , Glándulas Mamarias Animales/fisiopatología , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/fisiopatología , Ratones , Proteína Plasmática A Asociada al Embarazo/metabolismo , Proteolisis , Transducción de Señal , Somatomedinas/metabolismo , Microambiente Tumoral/genética
9.
EMBO Rep ; 21(4): e48978, 2020 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-32090465

RESUMEN

Defects in the proteasome can result in pathological proteinopathies. However, the pathogenic role of sex- and tissue-specific sensitivity to proteotoxic stress remains elusive. Here, we map the proteasome activity across nine tissues, in male and female mice, and demonstrate strong sexual dimorphism in proteasome activity, where females have significantly higher activity in several tissues. Further, we report drastic differences in proteasome activity among tissues, independently of proteasome concentration, which are exacerbated under stress conditions. Sexual dimorphism in proteasome activity is confirmed in a SOD1 ALS mouse model, in which the spinal cord, a tissue with comparatively low proteasome activity, is severely affected. Our results offer mechanistic insight into tissue-specific sensitivities to proteostasis stress and into sex differences in the progression of neurodegenerative proteinopathies.


Asunto(s)
Esclerosis Amiotrófica Lateral , Caracteres Sexuales , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Transgénicos , Complejo de la Endopetidasa Proteasomal/genética , Agregado de Proteínas , Superóxido Dismutasa/genética , Superóxido Dismutasa-1/genética
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