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1.
Food Chem Toxicol ; 186: 114540, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38387520

ABSTRACT

Benzophenone-3 (also referred to as oxybenzone) is a putative endocrine disrupting chemical and common ingredient in sunscreens and other personal care products. We previously showed that benzophenone-3 was promotional for epithelial tumorigenesis in mice fed adult high-fat diet, while protective against the incidence of more aggressive spindle cell tumors in the same treatment group. In this study, we show that benzophenone-3 reduces epithelial to mesenchymal transition in the epithelial tumors of these mice. This reduction in epithelial to mesenchymal transition is associated with altered expression of several genes involved in regulation of angiogenesis and epithelial to mesenchymal transition. Among the genes altered in expression, Timp1 is of particular interest because benzophenone-3 suppressed both migration and Timp1 expression in a mammary tumor cell line that displays epithelial to mesenchymal transition characteristics. These alterations in gene expression plausibly stabilize the vasculature of epithelial carcinomas and contribute to benzophenone-3 promotion of epithelial tumors, while at the same time suppress epithelial to mesenchymal transition and suppress incidence of spindle cell tumors.


Subject(s)
Benzophenones , Carcinoma , Epithelial-Mesenchymal Transition , Mice , Animals , Cell Transformation, Neoplastic , Carcinogenesis/genetics , Neovascularization, Pathologic , Cell Line, Tumor
2.
Fam Process ; 62(4): 1290-1306, 2023 12.
Article in English | MEDLINE | ID: mdl-37924221

ABSTRACT

We describe Richard Schwartz's development of the Internal Family Systems model (IFS) from his position as a Structural/Strategic family therapist. Four decades ago, Schwartz struggled to help clients who exhibited serious risk of harm to self and others. Through a process of inquiry, he began to work with the positive intentions behind his most challenging clients' harmful thoughts and behaviors. He applied foundational ideas from family systems thinking to patterns of internal experiences. As he experimented with ways of applying these ideas, he created an approach to healing. We summarize the IFS model delineating ways a range of family systems theory and practice inform its development and contribute to its best practice. Our purposes are to inform IFS practitioners who are not trained in foundational family systems models as well as to acknowledge the significant contributions family therapy theories made in the development and best practice of the IFS model.


Subject(s)
Family , Psychoanalytic Theory , Humans , Family/psychology
3.
Article in English | MEDLINE | ID: mdl-37593105

ABSTRACT

Environmental chemicals are a persistent and pervasive part of everyday life. A subset of environmental chemicals are xenoestrogens, compounds that bind to the estrogen receptor (ER) and drive estrogen-related processes. One such chemical, benzophenone-3 (BP3), is a common chemical in sunscreen. It is a potent UV protectant but also is quickly absorbed through the skin. While it has been approved by the FDA, there is a renewed interest in the safety of BP3, particularly in relation to breast cancer. The focus of this study was to examine the impact that BP3 has on triple negative breast cancer (TNBC) through alterations to cells in the immune microenvironment. In this study, we exposed female mice to one of two doses of BP3 before injecting them with a TNBC cell line. Several immune endpoints were examined both in the primary tissues and from in vitro studies of T cell behavior. Our studies revealed that in the lung tumor microenvironment, exposure to BP3 not only increased the number of metastases, but also the total area of tumor coverage. We also found that BP3 caused alterations in immune populations in a tissue-dependent manner, particularly in T cells. Taken together, our data suggest that while BP3 may not directly affect the proliferation of TNBC, growth and metastasis of TNBC-derived tumors can be altered by BP3 exposures via the alterations in the immune populations of the tumor microenvironment.

4.
Nat Commun ; 13(1): 6007, 2022 10 12.
Article in English | MEDLINE | ID: mdl-36224200

ABSTRACT

Virus infection affects cellular proteostasis and provides an opportunity to study this cellular process under perturbation. The proteostasis network in the endoplasmic reticulum (ER) is composed of the calnexin cycle, and the two protein degradation pathways ER-associated protein degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD/ER-phagy/reticulophagy). Here we show that calnexin and calreticulin trigger Zaire Ebolavirus (EBOV) glycoprotein GP1,2 misfolding. Misfolded EBOV-GP1,2 is targeted by ERAD machinery, but this results in lysosomal instead of proteasomal degradation. Moreover, the ER Ub ligase RNF185, usually associated with ERAD, polyubiquitinates EBOV-GP1,2 on lysine 673 via ubiquitin K27-linkage. Polyubiquinated GP1,2 is subsequently recruited into autophagosomes by the soluble autophagy receptor sequestosome 1 (SQSTM1/p62), in an ATG3- and ATG5-dependent manner. We conclude that EBOV hijacks all three proteostasis mechanisms in the ER to downregulate GP1,2 via polyubiquitination and show that this increases viral fitness. This study identifies linkages among proteostasis network components previously thought to function independently.


Subject(s)
Hemorrhagic Fever, Ebola , Proteostasis , Autophagy , Calnexin/metabolism , Calreticulin/metabolism , Endoplasmic Reticulum-Associated Degradation , Humans , Ligases/metabolism , Lysine/metabolism , Mitochondrial Proteins/metabolism , Molecular Chaperones/metabolism , Sequestosome-1 Protein/genetics , Sequestosome-1 Protein/metabolism , Ubiquitin/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism
5.
Reprod Toxicol ; 111: 184-193, 2022 08.
Article in English | MEDLINE | ID: mdl-35690277

ABSTRACT

While mammographic breast density is associated with breast cancer risk in humans, there is no comparable surrogate risk measure in mouse and rat mammary glands following various environmental exposures. In the current study, mammary glands from mice and rats subjected to reproductive factors and exposures to environmental chemicals that have been shown to influence mammary gland development and/or susceptibility to mammary tumors were evaluated for histologic density by manual and automated digital methods. Digital histological density detected changes due to hormonal stimuli/reproductive factors (parity), dietary fat, and exposure to environmental chemicals, such as benzophenone-3 and a combination of perfluorooctanoic acid and zeranol. Thus, digital analysis of mammary gland density offers a high throughput method that can provide a highly reproducible means of comparing a measure of histological density across independent experiments, experimental systems, and laboratories. This methodology holds promise for the detection of environmental impacts on mammary gland structure in mice and rats that may be comparable to human breast density, thus potentially allowing comparisons between rodent models and human breast cancer studies.


Subject(s)
Breast Neoplasms , Mammary Glands, Animal , Animals , Breast Density , Environment , Female , Humans , Mice , Pregnancy , Rats , Rodentia
6.
Autophagy ; 18(10): 2350-2367, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35130104

ABSTRACT

Zaire ebolavirus (EBOV) causes a severe hemorrhagic fever in humans and non-human primates with high morbidity and mortality. EBOV infection is dependent on its structural glycoprotein (GP), but high levels of GP expression also trigger cell rounding, detachment, and downregulation of many surface molecules that is thought to contribute to its high pathogenicity. Thus, EBOV has evolved an RNA editing mechanism to reduce its GP expression and increase its fitness. We now report that the GP expression is also suppressed at the protein level in cells by protein disulfide isomerases (PDIs). Although PDIs promote oxidative protein folding by catalyzing correct disulfide formation in the endoplasmic reticulum (ER), PDIA3/ERp57 adversely triggered the GP misfolding by targeting GP cysteine residues and activated the unfolded protein response (UPR). Abnormally folded GP was targeted by ER-associated protein degradation (ERAD) machinery and, unexpectedly, was degraded via the macroautophagy/autophagy-lysosomal pathway, but not the proteasomal pathway. PDIA3 also decreased the GP expression from other ebolavirus species but increased the GP expression from Marburg virus (MARV), which is consistent with the observation that MARV-GP does not cause cell rounding and detachment, and MARV does not regulate its GP expression via RNA editing during infection. Furthermore, five other PDIs also had a similar inhibitory activity to EBOV-GP. Thus, PDIs negatively regulate ebolavirus glycoprotein expression, which balances the viral life cycle by maximizing their infection but minimizing their cellular effect. We suggest that ebolaviruses hijack the host protein folding and ERAD machinery to increase their fitness via reticulophagy during infection.Abbreviations: 3-MA: 3-methyladenine; 4-PBA: 4-phenylbutyrate; ACTB: ß-actin; ATF: activating transcription factor; ATG: autophagy-related; BafA1: bafilomycin A1; BDBV: Bundibugyo ebolavirus; CALR: calreticulin; CANX: calnexin; CHX: cycloheximide; CMA: chaperone-mediated autophagy; ConA: concanamycin A; CRISPR: clusters of regularly interspaced short palindromic repeats; Cas9: CRISPR-associated protein 9; dsRNA: double-stranded RNA; EBOV: Zaire ebolavirus; EDEM: ER degradation enhancing alpha-mannosidase like protein; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; Env: envelope glycoprotein; ER: endoplasmic reticulum; ERAD: ER-associated protein degradation; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; GP: glycoprotein; HA: hemagglutinin; HDAC6: histone deacetylase 6; HMM: high-molecular-mass; HIV-1: human immunodeficiency virus type 1; HSPA5/BiP: heat shock protein family A (Hsp70) member 5; IAV: influenza A virus; IP: immunoprecipitation; KIF: kifenesine; Lac: lactacystin; LAMP: lysosomal associated membrane protein; MAN1B1/ERManI: mannosidase alpha class 1B member 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MARV: Marburg virus; MLD: mucin-like domain; NHK/SERPINA1: alpha1-antitrypsin variant null (Hong Kong); NTZ: nitazoxanide; PDI: protein disulfide isomerase; RAVV: Ravn virus; RESTV: Reston ebolavirus; SARS-CoV: severe acute respiratory syndrome coronavirus; SBOV: Sudan ebolavirus; sGP: soluble GP; SQSTM1/p62: sequestosome 1; ssGP: small soluble GP; TAFV: Taï Forest ebolavirus; TIZ: tizoxanide; TGN: thapsigargin; TLD: TXN (thioredoxin)-like domain; Ub: ubiquitin; UPR: unfolded protein response; VLP: virus-like particle; VSV: vesicular stomatitis virus; WB: Western blotting; WT: wild-type; XBP1: X-box binding protein 1.


Subject(s)
Autophagy , Ebolavirus , Actins/metabolism , Animals , CRISPR-Associated Protein 9/genetics , CRISPR-Associated Protein 9/metabolism , CRISPR-Associated Protein 9/pharmacology , Calnexin/metabolism , Calreticulin/genetics , Calreticulin/metabolism , Calreticulin/pharmacology , Cycloheximide , Cysteine/metabolism , Disulfides , Endoplasmic Reticulum/metabolism , Glycoproteins/metabolism , Heat-Shock Proteins/metabolism , Hemagglutinins/metabolism , Hemagglutinins/pharmacology , Histone Deacetylase 6/genetics , Intercellular Signaling Peptides and Proteins , Lysosomal Membrane Proteins/metabolism , Lysosomes/metabolism , Microtubule-Associated Proteins/metabolism , Mucins/genetics , Mucins/metabolism , Mucins/pharmacology , Prokaryotic Initiation Factor-2/genetics , Prokaryotic Initiation Factor-2/metabolism , Prokaryotic Initiation Factor-2/pharmacology , Protein Disulfide-Isomerases/genetics , Protein Disulfide-Isomerases/metabolism , RNA, Double-Stranded/metabolism , RNA, Double-Stranded/pharmacology , Sequestosome-1 Protein/metabolism , Thapsigargin/metabolism , Thapsigargin/pharmacology , Thioredoxins/genetics , Thioredoxins/metabolism , Thioredoxins/pharmacology , Ubiquitins/metabolism , X-Box Binding Protein 1/metabolism , alpha-Mannosidase/genetics , alpha-Mannosidase/metabolism , alpha-Mannosidase/pharmacology
7.
Int J Environ Health Res ; 32(10): 2135-2148, 2022 Oct.
Article in English | MEDLINE | ID: mdl-34313174

ABSTRACT

Experimental studies have suggested benzophenone-3 (BP-3), a sunscreen ingredient, may have endocrine-disrupting properties. A cohort of girls were recruited at ages 6-7 years and returned semi-annually for pubertal maturation staging, provided blood for serum hormone analyses [estradiol, estrone, testosterone, dehydroepiandrosterone-sulfate (DHEA-S)], and urine to measure BP-3 concentrations. We found a significant negative linear association between amount of reported sunscreen use and testosterone levels at the onset of puberty (N = 157, adjusted ß = -0.0163, 97.5% CI:-0.0300,-0.0026). The 2nd quartile of the BP-3 biomarker had earlier thelarche compared to the 1st quartile (N = 282, adjusted HR = 1.584, 97.5% CI:1.038,2.415). Results suggest that higher report of sunscreen use may be associated with lower testosterone levels at thelarche and a non-linear relationship between the BP-3 urinary biomarker and onset of puberty, although the clinical significance of the finding is limited and may be a random effect. Improved methods of BP-3 exposure characterization are needed.


Subject(s)
Estrone , Sunscreening Agents , Benzophenones , Biomarkers , Child , Dehydroepiandrosterone , Estradiol , Female , Gonadal Steroid Hormones , Humans , Longitudinal Studies , Sulfates , Surveys and Questionnaires , Testosterone
8.
Oncotarget ; 11(48): 4465-4478, 2020 Dec 01.
Article in English | MEDLINE | ID: mdl-33400736

ABSTRACT

Benzophenone-3 is a putative endocrine disrupting chemical and common ingredient in sunscreens. The potential of endocrine disrupting chemicals to act as agonists or antagonists in critical hormonally regulated processes, such as mammary gland development and mammary tumorigenesis, demands evaluation of its potential in promoting breast cancer. This study identifies the effects of BP-3 on mammary tumorigenesis with high-fat diet during puberty versus adulthood in Trp53-null transplant BALB/c mice. Benzophenone-3 exposure yielded levels in urine similar to humans subjected to heavy topical sunscreen exposure. Benzophenone-3 was protective for epithelial tumorigenesis in mice fed lifelong low-fat diet, while promotional for epithelial tumorigenesis in mice fed adult high-fat diet. Benzophenone-3 increased tumor cell proliferation, decreased tumor cell apoptosis, and increased tumor vascularity dependent on specific dietary regimen and tumor histopathology. Even in instances of an ostensibly protective effect, other parameters suggest greater risk. Although benzophenone-3 seemed protective on low-fat diet, spindle cell tumors arising in these mice showed increased proliferation and decreased apoptosis. This points to a need for further studies of benzophenone-3 in both animal models and humans as a potential breast cancer risk factor, as well as a more general need to evaluate endocrine disrupting chemicals in varying dietary contexts.

9.
J Virol ; 93(14)2019 07 15.
Article in English | MEDLINE | ID: mdl-31043528

ABSTRACT

Serine incorporator 5 (SERINC5) is a recently identified restriction factor that strongly blocks HIV-1 entry but is counteracted by Nef. Notably, tier 1 HIV-1 Env proteins are sensitive to SERINC5, whereas the majority of tier 2/3 Env proteins are resistant to SERINC5, when viruses are produced from CD4-negative cells and tested by a single-round replication assay. Here, we investigated the Env-dependent SERINC5 antiviral mechanism by comparing tier 1 NL Env with tier 3 AD8 Env proteins. We found that when NL and AD8 viruses were inoculated into CD4+ T cells and human peripheral blood mononuclear cells (PBMCs), the propagation of the two viruses was restricted to a similar level when Nef was not expressed. Using a bimolecular fluorescence complementation (BiFC) assay, we detected Env-Env association and Env-SERINC5 interactions. A much greater level of NL Env-SERINC5 interactions was detected than was AD8 Env-SERINC5 interactions, which was further validated by immunoprecipitation assays. In addition, SERINC5 dissociated the NL Env trimeric complex more effectively than the AD8 Env trimeric complex when CD4 was not expressed. However, when CD4 was expressed, SERINC5 became more capable of interacting with AD8 Env and dissociating its trimeric complex. Moreover, AD8 and several other tier 2/3 viruses produced in the presence of CD4 became sensitive to SERINC5 when measured by the single-round replication assay. Because tier 1 and tier 2/3 Env trimers have open and closed conformations, respectively, and CD4 opens the closed conformation, we conclude that SERINC5 selectively dissociates Env trimers with an open conformation to restrict HIV-1 replication.IMPORTANCE Restriction factors provide the first line of defense against retrovirus infection by posing several blocks to the viral replication cycle. SERINC5 is a novel restriction factor that strongly blocks HIV-1 entry, although it is counteracted by Nef. Currently, it is still unclear how HIV-1 entry is blocked by SERINC5. Notably, this entry block is dependent on viral Env proteins. Laboratory-adapted HIV-1 strains are sensitive, whereas primary isolates are highly resistant to SERINC5. Env proteins mediate virus entry via extensive conformational rearrangements from a closed ground state to a CD4-bound open state. We detected Env-Env associations and Env-SERINC5 interactions in live cells by a novel bimolecular fluorescence assay. We demonstrate that CD4 expression increases the Env sensitivity to SERINC5 and allows SERINC5 to dissociate the Env complex, suggesting that SERINC5 restriction is dependent on Env conformation. Our results provide new insights into the poorly defined Env-dependent SERINC5 antiviral mechanism.


Subject(s)
CD4 Antigens , CD4-Positive T-Lymphocytes , Gene Expression Regulation/immunology , HIV-1 , Membrane Proteins , env Gene Products, Human Immunodeficiency Virus , CD4 Antigens/genetics , CD4 Antigens/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , HEK293 Cells , HIV-1/genetics , HIV-1/immunology , Humans , Jurkat Cells , Membrane Proteins/genetics , Membrane Proteins/immunology , Protein Structure, Quaternary , env Gene Products, Human Immunodeficiency Virus/genetics , env Gene Products, Human Immunodeficiency Virus/immunology
10.
Mol Cell Endocrinol ; 477: 57-69, 2018 12 05.
Article in English | MEDLINE | ID: mdl-29870755

ABSTRACT

CCAAT/enhancer binding protein ß (C/EBPß) is required for murine mammary ductal morphogenesis and alveologenesis. Progesterone is critical for proliferation and alveologenesis in adult mammary glands, and there is a similar requirement for progesterone receptor isoform B (PRB) in alveologenesis. We examined C/EBPß regulation of PR expression. All three C/EBPß isoforms, including typically inhibitory LIP, transactivated the PR promoter. LIP, particularly, strongly synergized with c-Jun to drive PR transcription. Endogenous C/EBPß and c-Jun stimulated a PR promoter-reporter and these two factors showed promoter occupancy on the endogenous PR gene. Additionally, LIP overexpression elevated endogenous PR protein expression. In pregnancy, both PRB and the relative abundance of LIP among C/EBPß isoforms increase. Consistent with a role in PRB expression, in vivo C/EBPß and PR isoform A expression showed mutually exclusive localization in mammary epithelium, while C/EBPß and PRB largely co-localized. We suggest a critical role for C/EBPß, particularly LIP, in PRB expression.


Subject(s)
CCAAT-Enhancer-Binding Protein-beta/metabolism , Gene Expression Regulation , Proto-Oncogene Proteins c-jun/metabolism , Receptors, Progesterone/genetics , Animals , Cell Line , Female , Genes, Reporter , Mice, Inbred BALB C , Promoter Regions, Genetic/genetics , Protein Binding , Receptors, Progesterone/metabolism
11.
Transl Oncol ; 11(2): 518-527, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29524829

ABSTRACT

Increased proliferation and breast cancer risk has been observed in postmenopausal women receiving estrogen (E) + progestin hormone replacement therapy (HRT). Progestin action is mediated through two progesterone receptor (PR) isoforms, PRA and PRB, with unique transcriptional activity and function. The current study examines hormonal regulation of PR isoforms in the normal postmenopausal human breast and the mechanism by which progestins increase proliferation and breast cancer risk. Archival benign breast biopsies from postmenopausal and premenopausal women, and luminal breast tumor biopsies from postmenopausal women, were analyzed for regulation of PRA and PRB expression by E and E+medroxyprogesterone acetate (MPA). In the postmenopausal breast without HRT, PRA and PRB expression was decreased compared to the premenopausal breast. Both E (n = 12) and E+MPA (n = 13) HRT in the postmenopausal breast were associated with increased PRA and PRB expression, increased nuclear cyclin E expression, and decreased nuclear p27 expression compared to no HRT (n = 16). With E+MPA HRT, there was a further decrease in nuclear p27 and increased Receptor Activator of NF-kappa B Ligand (RANKL) expression compared to E-alone HRT. In luminal breast cancers, E+MPA HRT (n = 6) was also associated with decreased nuclear expression of the cell cycle inhibitor p27 compared to E HRT (n = 6), but was not associated with increased proliferation. These results suggest that p27 mediates progestin-induced proliferation in the normal human breast and that regulation of this proliferative response by E+MPA is lost in breast tumors.

12.
J Virol ; 92(1)2018 01 01.
Article in English | MEDLINE | ID: mdl-29046440

ABSTRACT

Innate immunity provides an immediate defense against infection after host cells sense danger signals from microbes. Endoplasmic reticulum (ER) stress arises from accumulation of misfolded/unfolded proteins when protein load overwhelms the ER folding capacity, which activates the unfolded protein response (UPR) to restore ER homeostasis. Here, we show that a mechanism for antiviral innate immunity is triggered after the ER stress pathway senses viral glycoproteins. When hemagglutinin (HA) glycoproteins from influenza A virus (IAV) are expressed in cells, ER stress is induced, resulting in rapid HA degradation via proteasomes. The ER-associated protein degradation (ERAD) pathway, an important UPR function for destruction of aberrant proteins, mediates HA degradation. Three class I α-mannosidases were identified to play a critical role in the degradation process, including EDEM1, EDEM2, and ERManI. HA degradation requires either ERManI enzymatic activity or EDEM1/EDEM2 enzymatic activity when ERManI is not expressed, indicating that demannosylation is a critical step for HA degradation. Silencing of EDEM1, EDEM2, and ERManI strongly increases HA expression and promotes IAV replication. Thus, the ER stress pathway senses influenza HA as "nonself" or misfolded protein and sorts HA to ERAD for degradation, resulting in inhibition of IAV replication.IMPORTANCE Viral nucleic acids are recognized as important inducers of innate antiviral immune responses that are sensed by multiple classes of sensors, but other inducers and sensors of viral innate immunity need to be identified and characterized. Here, we used IAV to investigate how host innate immunity is activated. We found that IAV HA glycoproteins induce ER stress, resulting in HA degradation via ERAD and consequent inhibition of IAV replication. In addition, we have identified three class I α-mannosidases, EDEM1, EDEM2, and ERManI, which play a critical role in initiating HA degradation. Knockdown of these proteins substantially increases HA expression and IAV replication. The enzymatic activities and joint actions of these mannosidases are required for this antiviral activity. Our results suggest that viral glycoproteins induce a strong innate antiviral response through activating the ER stress pathway during viral infection.


Subject(s)
Endoplasmic Reticulum Stress , Endoplasmic Reticulum-Associated Degradation , Endoplasmic Reticulum/metabolism , Glycoproteins/immunology , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Immunity, Innate , Proteolysis , Glycoproteins/genetics , HEK293 Cells , Hemagglutinin Glycoproteins, Influenza Virus/chemistry , Hemagglutinin Glycoproteins, Influenza Virus/metabolism , Humans , Influenza A virus/chemistry , Influenza A virus/immunology , Membrane Proteins/metabolism , Protein Folding , Protein Transport , Virus Replication , alpha-Mannosidase/metabolism
13.
Transl Oncol ; 10(6): 928-935, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29024822

ABSTRACT

Premenopausal breast cancer is associated with increased animal fat consumption among normal-weight but not overweight women. Our previous findings in obesity-resistant BALB/c mice showed that a diet high in saturated animal fat (HFD) promotes mammary tumorigenesis in both DMBA carcinogenesis and Trp53-null transplant models. Having made these observations in BALB/c mice, which have very modest HFD weight gain, we determined the effects of HFD in FVB mice, which gain significant weight on HFD. Three-week-old FVB mice fed a low-fat diet or HFD were subjected to 7,12-dimethylbenz[a]anthracene-induced carcinogenesis. Like BALB/c mice, HFD promoted mammary tumorigenesis. Development of tumors largely occurred prior to mice becoming obese, indicating the role of animal-derived HFD rather than resulting obesity in tumor promotion. Also similar to BALB/c mice, early-occurring adenosquamous mammary tumors were abundant among HFD-fed FVB mice. Tumors from HFD mice also had increased intra-tumor M2 macrophages. Prior to tumor development, HFD accelerated normal mammary gland development and increased mammary M2 macrophages, similarly to BALB/c mice. The promotional effects of puberty-initiated HFD on carcinogen-induced mammary cancer are thus largely weight gain-independent. Like BALB/c mice, HFD promoted adenosquamous tumors, suggesting a role for early age HFD in promoting this subtype of triple negative mammary cancer. M2 macrophage recruitment was common to both mouse strains. We speculate that a similar effect of HFD on immune function may contribute to epidemiological findings of increased breast cancer risk in young, premenopausal, normal-weight women who consume a diet high in saturated animal fat.

14.
J Pediatr Adolesc Gynecol ; 30(5): 535-539, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28216130

ABSTRACT

STUDY OBJECTIVE: Amphiregulin is a member of the epidermal growth factor family. In breast tissue, amphiregulin is a mediator of estrogen and progesterone signaling. The objectives were to examine the relationship of amphiregulin levels during peripuberty with estrogen levels. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: The participants in this analysis were a subset from a longitudinal study of pubertal maturation, the Breast Cancer and the Environment Research Program. They were recruited between ages 3 and 7 years. Blood specimens were selected for hormone analysis between 24 months before and 6 months after breast development. Serum amphiregulin levels were analyzed using enzyme-linked immunosorbent assay. RESULTS: Amphiregulin levels were measured in 188 girls; 8.5% had a maternal history of breast cancer, and 30.9% of samples were below the limit of detection. Amphiregulin levels were greatest at 18 months before the onset of breast development (P < .006), and the rise in estrone levels between -24 and -18 months was correlated with the increase in amphiregulin levels in the same time period (P = .0002). After adjustment for time relative to breast development, amphiregulin levels were associated with maternal breast cancer (P = .024). Tracking of amphiregulin levels was highly significant (P < .0001) within a given individual. CONCLUSION: Amphiregulin levels peaked at 18 months before the onset of breast development, were temporally related to the rise in serum estrone, and were significantly associated with maternal history of breast cancer. Elevated amphiregulin levels at puberty might be a predictor of increased breast cancer risk.


Subject(s)
Amphiregulin/blood , Estrogens/blood , Puberty/blood , Sexual Maturation/physiology , Biomarkers/analysis , Breast/growth & development , Child , Child, Preschool , Enzyme-Linked Immunosorbent Assay , Female , Humans , Longitudinal Studies
15.
Oncotarget ; 7(50): 83409-83423, 2016 Dec 13.
Article in English | MEDLINE | ID: mdl-27825136

ABSTRACT

Premenopausal breast cancer is associated with increased animal fat consumption among normal weight, but not overweight women (Farvid et al., 2014). Our previous findings in obesity-resistant BALB/c mice similarly showed promotion of carcinogen-induced mammary tumorigenesis by a diet high in saturated animal fat (HFD). This effect was specific to pubertal versus adult HFD. This study identifies the effects of HFD during puberty versus adulthood in Trp53-null transplant BALB/c mice and investigates its mechanism of enhancing tumorigenesis. Either pubertal or adult HFD is sufficient to increase incidence of Trp53-null mammary tumors. Puberty-restricted HFD exposure promoted tumor cell proliferation, increased angiogenesis, and increased recruitment of total and M2 macrophages in epithelial tumors. Adult-restricted exposure to HFD similarly increased proliferation, angiogenesis, recruitment of total and M2 macrophages, and additionally reduced apoptosis. Adult HFD also increased incidence of spindle cell carcinomas resembling claudin-low breast cancer, and thus adult HFD in the Trp53-null transplantation system may be a useful model for human claudin low breast cancer. Importantly, these results on Trp53-null and our prior studies on DMBA-induced mammary tumorigenesis demonstrate a pubertal window of susceptibility to the promotional effects of HFD, indicating the potential of early life dietary intervention to reduce breast cancer risk.


Subject(s)
Carcinoma/etiology , Cell Transformation, Neoplastic/metabolism , Diet, High-Fat/adverse effects , Mammary Glands, Animal/metabolism , Mammary Neoplasms, Experimental/etiology , Tumor Suppressor Protein p53/deficiency , Age Factors , Animals , Apoptosis , Carcinoma/genetics , Carcinoma/metabolism , Carcinoma/pathology , Cell Proliferation , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Female , Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , Macrophages/metabolism , Macrophages/pathology , Mammary Glands, Animal/pathology , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Mice, Inbred BALB C , Mice, Knockout , Neovascularization, Pathologic , Phenotype , Risk Factors , Sexual Development , Time Factors , Tumor Suppressor Protein p53/genetics
16.
Breast Cancer Res ; 17(1): 138, 2015 Nov 02.
Article in English | MEDLINE | ID: mdl-26526858

ABSTRACT

INTRODUCTION: Increased animal fat consumption is associated with increased premenopausal breast cancer risk in normal weight, but not overweight, women. This agrees with our previous findings in obesity-resistant BALB/c mice, in which exposure to a high saturated animal fat diet (HFD) from peripuberty through adulthood promoted mammary tumorigenesis. Epidemiologic and animal studies support the importance of puberty as a life stage when diet and environmental exposures affect adult breast cancer risk. In this study, we identified the effects of peripubertal exposure to HFD and investigated its mechanism of enhancing tumorigenesis. METHODS: Three-week-old BALB/c mice fed a low-fat diet (LFD) or HFD were subjected to 7,12-dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis. At 9 weeks of age, half the mice on LFD were switched to HFD (LFD-HFD group) and half the mice on HFD were switched to LFD (HFD-LFD group). Tumor gene expression was evaluated in association with diet and tumor latency. RESULTS: The peripubertal HFD reduced the latency of DMBA-induced mammary tumors and was associated with tumor characteristics similar to those in mice fed a continuous HFD. Notably, short-latency tumors in both groups shared gene expression characteristics and were more likely to have adenosquamous histology. Both HFD-LFD and continuous HFD tumors showed similar gene expression patterns and early latency. Adult switch from HFD to LFD did not reverse peripubertal HFD tumor promotion. Increased proliferation, hyperplasia, and macrophages were present in mammary glands before tumor development, implicating these as possible effectors of tumor promotion. Despite a significant interaction between pubertal diet and carcinogens in tumor promotion, peripubertal HFD by itself produced persistent macrophage recruitment to mammary glands. CONCLUSIONS: In obesity-resistant mice, peripubertal HFD is sufficient to irreversibly promote carcinogen-induced tumorigenesis. Increased macrophage recruitment is likely a contributing factor. These results underscore the importance of early life exposures to increased adult cancer risk and are consistent with findings that an HFD in normal weight premenopausal women leads to increased breast cancer risk. Notably, short-latency tumors occurring after peripubertal HFD had characteristics similar to human basal-like breast cancers that predominantly develop in younger women.


Subject(s)
Carcinogenesis/metabolism , Carcinoma, Adenosquamous/etiology , Diet, High-Fat/adverse effects , Mammary Neoplasms, Experimental/etiology , Animals , Carcinoma, Adenosquamous/metabolism , Chemokines/metabolism , Female , Mammary Glands, Animal/growth & development , Mammary Glands, Animal/metabolism , Mammary Glands, Animal/pathology , Mammary Neoplasms, Experimental/metabolism , Mice, Inbred BALB C , Sexual Maturation , Transcriptome , beta Catenin/metabolism
17.
Endocrinology ; 155(6): 2301-13, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24693965

ABSTRACT

It is well documented that macrophages and eosinophils play important roles in normal murine pubertal mammary gland development. Although it is accepted that estrogen (E) and progesterone (P) are key players in mammary gland development, the roles these hormones might play in regulating the actions of leukocytes in that process is an understudied area. We show here that P and E, respectively, induce unique, but overlapping, sets of proinflammatory and angiogenic cytokines and chemokines, in the pubertal female BALB/c mammary gland, as well as induce infiltration of macrophages and eosinophils to the mammary periepithelium. This extends earlier studies showing P induction of proinflammatory products in pubertal and adult mammary epithelial organoids and P-induced in vivo infiltration of leukocytes to the adult mammary periepithelium. Importantly, epidermal growth factor receptor-signaling, which is likely mediated by amphiregulin (Areg), a downstream mediator of E and P, is both necessary and sufficient for both E- and P-induced recruitment of macrophages and eosinophils to the pubertal mammary periepithelium. We further show that receptor activator of nuclear factor κB ligand (RANKL), although not sufficient of itself to cause macrophage and eosinophil recruitment, contributes to an optimal response to P. The potency of Areg is highlighted by the fact that it is sufficient to induce macrophage and eosinophil recruitment at levels equivalent to that induced by either E or P. Our finding of a dominant role for Areg in hormonally induced leukocyte recruitment to the pubertal mammary gland parallels its dominance in regulating ductal outgrowth and its role in P-induced proliferation in the pubertal gland.


Subject(s)
ErbB Receptors/metabolism , Estrogens/pharmacology , Leukocytes/cytology , Mammary Glands, Animal/drug effects , Mammary Glands, Animal/metabolism , Progesterone/pharmacology , Acid Phosphatase/pharmacology , Animals , ErbB Receptors/genetics , Female , Fluorescent Antibody Technique , Isoenzymes/pharmacology , Mice , Mice, Inbred BALB C , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Tartrate-Resistant Acid Phosphatase
18.
Breast Cancer Res ; 15(5): R100, 2013.
Article in English | MEDLINE | ID: mdl-24156623

ABSTRACT

INTRODUCTION: Epidemiological studies linking dietary fat intake and obesity to breast cancer risk have produced inconsistent results. This may be due to the difficulty of dissociating fat intake from obesity, and/or the lack of defined periods of exposure in these studies. The pubertal mammary gland is highly sensitive to cancer-causing agents. We assessed how high fat diet (HFD) affects inflammation, proliferative, and developmental events in the pubertal gland, since dysregulation of these can promote mammary tumorigenesis. To test the effect of HFD initiated during puberty on tumorigenesis, we utilized BALB/c mice, for which HFD neither induces obesity nor metabolic syndrome, allowing dissociation of HFD effects from other conditions associated with HFD. METHODS: Pubertal BALB/c mice were fed a low fat diet (12% kcal fat) or a HFD (60% kcal fat), and subjected to carcinogen 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis. RESULTS: HFD elevated mammary gland expression of inflammatory and growth factor genes at 3 and 4 weeks of diet. Receptor activator of nuclear factor kappa-B ligand (RANKL), robustly induced at 4 weeks, has direct mitogenic activity in mammary epithelial cells and, as a potent inducer of NF-κB activity, may induce inflammatory genes. Three weeks of HFD induced a transient influx of eosinophils into the mammary gland, consistent with elevated inflammatory factors. At 10 weeks, prior to the appearance of palpable tumors, there were increased numbers of abnormal mammary epithelial lesions, enhanced cellular proliferation, increased growth factors, chemokines associated with immune-suppressive regulatory T cells, increased vascularization, and elevated M2 macrophages. HFD dramatically reduced tumor latency. Early developing tumors were more proliferative and were associated with increased levels of tumor-related growth factors, including increased plasma levels of HGF in tumor-bearing animals. Early HFD tumors also had increased vascularization, and more intra-tumor and stromal M2 macrophages. CONCLUSIONS: Taken together in this non-obesogenic context, HFD promotion of inflammatory processes, as well as local and systemically increased growth factor expression, are likely responsible for the enhanced tumorigenesis. It is noteworthy that although DMBA mutagenesis is virtually random in its targeting of genes in tumorigenesis, the short latency tumors arising in animals on HFD showed a unique gene expression profile, highlighting the potent overarching influence of HFD.


Subject(s)
Breast Neoplasms/etiology , Diet, High-Fat , Mammary Neoplasms, Experimental/etiology , Sexual Maturation , Animals , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Cell Proliferation , Cytokines/metabolism , Female , Gene Expression Profiling , Hormones/blood , Humans , Inflammation/genetics , Inflammation/metabolism , Inflammation Mediators/metabolism , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/mortality , Mammary Neoplasms, Experimental/pathology , Mice , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Signal Transduction , Time Factors , Tumor Microenvironment
19.
J Rheumatol ; 40(11): 1831-41, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23950186

ABSTRACT

OBJECTIVE: To conduct a proof-of-concept randomized trial of an Internal Family Systems (IFS) psychotherapeutic intervention on rheumatoid arthritis (RA) disease activity and psychological status. METHODS: Patients with RA were randomized to either an IFS group for 9 months (n = 39) or an education (control) group (n = 40) that received mailed materials on RA symptoms and management. The groups were evaluated every 3 months until intervention end and 1 year later. Self-assessed joint pain (RA Disease Activity Index joint score), Short Form-12 physical function score, visual analog scale for overall pain and mental health status (Beck Depression Inventory, and State Trait Anxiety Inventory) were assessed. The 28-joint Disease Activity Score-C-reactive Protein 4 was determined by rheumatologists blinded to group assignment. Treatment effects were estimated by between-group differences, and mixed model repeated measures compared trends between study arms at 9 months and 1 year after intervention end. RESULTS: Of 79 participants randomized, 68 completed the study assessments and 82% of the IFS group completed the protocol. Posttreatment improvements favoring the IFS group occurred in overall pain [mean treatment effects -14.9 (29.1 SD); p = 0.04], and physical function [14.6 (25.3); p = 0.04]. Posttreatment improvements were sustained 1 year later in self-assessed joint pain [-0.6 (1.1); p = 0.04], self-compassion [1.8 (2.8); p = 0.01], and depressive symptoms [-3.2 (5.0); p =0.01]. There were no sustained improvements in anxiety, self-efficacy, or disease activity. CONCLUSION: An IFS-based intervention is feasible and acceptable to patients with RA and may complement medical management of the disease. Future efficacy trials are warranted. ClinicalTrials.gov identifier: NCT00869349.


Subject(s)
Arthritis, Rheumatoid/therapy , Psychotherapy/methods , Self Efficacy , Adult , Aged , Arthritis, Rheumatoid/psychology , Female , Humans , Male , Middle Aged , Pain Measurement , Psychiatric Status Rating Scales , Self Care , Severity of Illness Index , Treatment Outcome
20.
J Clin Psychol ; 69(8): 805-16, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23813465

ABSTRACT

Clients come to psychotherapy intent on changing, rather than accepting, their unwanted behaviors, emotions, or thoughts. The problem often is, however, that their lack of self-acceptance is the primary obstacle to change. This article describes how one approach, the Internal Family Systems (IFS) model, fosters clients' acceptance of all parts of themselves no matter how destructive, and how that acceptance can lead to the transformation of those parts and, in turn, of other people.


Subject(s)
Adaptation, Psychological , Mind-Body Therapies , Psychotherapy/methods , Self Concept , Adult , Humans , Male , Obsessive-Compulsive Disorder/therapy
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