Androgen Receptor (AR) signaling is a critical driver of hormone-dependent prostate cancer and has also been proposed to have biological activity in female hormone-dependent cancers, including type I ...endometrial carcinoma (EMC). In this study, we evaluated the preclinical efficacy of a third-generation AR antagonist, enzalutamide, in a genetic mouse model of EMC, Sprr2f-Cre;Ptenfl/fl. In this model, ablation of Pten in the uterine epithelium leads to localized and distant malignant disease as observed in human EMC. We hypothesized that administering enzalutamide through the diet would temporarily decrease the incidence of invasive and metastatic carcinoma, while prolonged administration would result in development of resistance and loss of efficacy. Short-term treatment with enzalutamide reduced overall tumor burden through increased apoptosis but failed to prevent progression of invasive and metastatic disease. These results suggest that AR signaling may have biphasic, oncogenic and tumor suppressive roles in EMC that are dependent on disease stage. Enzalutamide treatment increased Progesterone Receptor (PR) expression within both stromal and tumor cell compartments. Prolonged administration of enzalutamide decreased apoptosis, increased tumor burden and resulted in the clonal expansion of tumor cells expressing high levels of p53 protein, suggestive of acquired Trp53 mutations. In conclusion, we show that enzalutamide induces apoptosis in EMC but has limited efficacy overall as a single agent. Induction of PR, a negative regulator of endometrial proliferation, suggests that adding progestin therapy to enzalutamide administration may further decrease tumor burden and result in a prolonged response.
Platelet-derived growth factor receptor-beta (PDGFRβ) is a receptor tyrosine kinase found in cells of mesenchymal origin such as fibroblasts and pericytes. Activation of this receptor is dependent on ...paracrine ligand induction, and its preferred ligand PDGFB is released by neighboring epithelial and endothelial cells. While expression of both PDGFRβ and PDGFB has been noted in patient breast tumors for decades, how PDGFB-to-PDGFRβ tumor-stroma signaling mediates breast cancer initiation, progression, and metastasis remains unclear. Here we demonstrate this paracrine signaling pathway that mediates both primary tumor growth and metastasis, specifically, metastasis to the brain. Elevated levels of PDGFB accelerated orthotopic tumor growth and intracranial growth of mammary tumor cells, while mesenchymal-specific expression of an activating mutant PDGFRβ (PDGFRβ
) exerted proproliferative signals on adjacent mammary tumor cells. Stromal expression of PDGFRβ
also promoted brain metastases of mammary tumor cells expressing high PDGFB when injected intravenously. In the brain, expression of PDGFRβ
was observed within a subset of astrocytes, and aged mice expressing PDGFRβ
exhibited reactive gliosis. Importantly, the PDGFR-specific inhibitor crenolanib significantly reduced intracranial growth of mammary tumor cells. In a tissue microarray comprised of 363 primary human breast tumors, high PDGFB protein expression was prognostic for brain metastases, but not metastases to other sites. Our results advocate the use of mice expressing PDGFRβ
in their stromal cells as a preclinical model of breast cancer-associated brain metastases and support continued investigation into the clinical prognostic and therapeutic use of PDGFB-to-PDGFRβ signaling in women with breast cancer. SIGNIFICANCE: These studies reveal a previously unknown role for PDGFB-to-PDGFRβ paracrine signaling in the promotion of breast cancer brain metastases and support the prognostic and therapeutic clinical utility of this pathway for patients.
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Heterozygous mutations in the
gene predispose women to breast and ovarian cancer, while biallelic BRCA1 mutations are a cause of Fanconi anemia (FA), a rare genetic disorder characterized by ...developmental abnormalities, early-onset bone marrow failure, increased risk of cancers, and hypersensitivity to DNA-crosslinking agents. BRCA1 is critical for homologous recombination of DNA double-strand breaks (DSB). Through its coiled-coil domain, BRCA1 interacts with an essential partner, PALB2, recruiting BRCA2 and RAD51 to sites of DNA damage. Missense mutations within the coiled-coil domain of BRCA1 (e.g., L1407P) that affect the interaction with PALB2 have been reported in familial breast cancer. We hypothesized that if PALB2 regulates or mediates BRCA1 tumor suppressor function, ablation of the BRCA1-PALB2 interaction may also elicit genomic instability and tumor susceptibility. We generated mice defective for the Brca1-Palb2 interaction (Brca1 L1363P in mice) and established MEF cells from these mice.
MEF exhibited hypersensitivity to DNA-damaging agents and failed to recruit Rad51 to DSB.
mice were viable but exhibited various FA symptoms including growth retardation, hyperpigmentation, skeletal abnormalities, and male/female infertility. Furthermore, all
mice exhibited macrocytosis and died due to bone marrow failure or lymphoblastic lymphoma/leukemia with activating Notch1 mutations. These phenotypes closely recapitulate clinical features observed in patients with FA. Collectively, this model effectively demonstrates the significance of the BRCA1-PALB2 interaction in genome integrity and provides an FA model to investigate hematopoietic stem cells for mechanisms underlying progressive failure of hematopoiesis and associated development of leukemia/lymphoma, and other FA phenotypes. SIGNIFICANCE: A new Brca1 mouse model for Fanconi anemia (FA) complementation group S provides a system in which to study phenotypes observed in human FA patients including bone marrow failure.
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Abstract
Rationale: African American women (AAW) have a higher incidence of triple negative breast cancer (TNBC), and higher mortality from breast cancer when compared to Caucasian women (CW). ...Epidemiological studies have shown that lack, or short duration, of breast-feeding, a more common practice among AAW than CW, may be one of the factors that increase the risk of TNBC. The pregnancy-lactation-involution cycle is a dynamic process where upon pregnancy, breast undergoes extensive proliferation and differentiation for milk production followed by apoptosis as it involutes to near pre-pregnant state. Prolonged breastfeeding results in gradual involution (GI) whereas no or short duration of breastfeeding leads to forced and abrupt involution (AI) of breast. We modeled GI and AI in wild-type FVB/N mice and reported that mammary glands of abruptly involuted mice had expansion of luminal progenitor (LP) cells over time and hyperplastic precancerous changes within 120 days postpartum1. In addition, there was increased Stat3 (Signal Transducer and Activator of Transcription 3) activation (pStat3Y705) in AI glands. Persistent Stat3 activation is linked to tumor cell proliferation, survival, invasion, and tumor-promoting inflammation2. In mice, Stat3 is required for the initiation and acute phase response during mammary gland involution and is crucial for the proliferation of LP cells3-5. We hypothesized that Stat3 activation plays a key role in the development of hyperplasia and fibrosis observed following AI.Methods: We bred Stat3Fl/Flmice with MMTV-Cre mice to induce mammary epithelial specific deletion of Stat3. Experimental (MMTV-Cre+;Stat3Fl/Fl) and control females (Stat3Fl/Fl) were bred once at 8 weeks of age and litter sizes were normalized to 6pups/dam within 24 hours of partum. With day of partum as day0, all 6 pups were removed on day7 and AI was initiated. Mammary glands were harvested on postpartum day28, day56, and day120. Florescence activated cell sorting (FACS) was performed to determine distribution of mammary epithelial subpopulations. Histological effects of Stat3 deletion on mammary gland involution was assessed via staining using haematoxylin and eosin (H&E), Masson’s Trichrome and immunostaining using anti-Ki67 and anti-Stat3 antibodies. Results: Stat3 deletion failed to abrogate the hyperplasia and collagen deposition we initially observed in our AI mice with intact Stat3 as determined by H&E and Trichrome stains. In addition, collagen deposition was further increased following Stat3 deletion, when compared to control cohort. FACS analysis demonstrated that Stat3 deletion resulted in reduction of LP cell population only at early timepoint (day28) but this population rebounded in glands by later timepoints. Stat3 deletion temporarily increased cell proliferation by Ki-67 staining at day28 and 56, with no difference observed between controls at day120. Conclusion: This is the first study showing results of mammary epithelial specific Stat3 deletion on long-term effect of AI. Contrary to our hypothesis, Stat3 deletion did not reduce the hyperplastic changes we observed following abrupt involution of mammary glands. Our findings indicate that Stat3 signaling may limit collagen formation within the mammary gland during abrupt involution. Stat3 is important for the maintenance of LP cells at early timepoints. Further studies are underway to determine the critical downstream events following Stat3 activation that limits long-term effects of abrupt involution. 1. Basree et. al. 2019, in press, Breast Cancer Research 2. Yu et. al. 2014 (PMID: 25342631) 3. Chapman et. al. 1999 (PMID: 10521404) 4. Hughes et. al. 2012 (PMID: 22081431)5. Staniszewska et. al. 2012 (PMID: 23285109)
Citation Format: Allen Zhang, Neelam Shinde, Christopher S Koivisto, Mustafa M Basree, Resham S Mawalkar, Hee K Kim, Gustavo Leone, Sarmila Majumder, Bhuvaneswari Ramaswamy. Mammary gland specific Stat3 deletion during involution results in distinct histological changes and higher collagen deposition abstract. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-07-11.
To prospectively determine temporal changes in regional cerebral perfusion in patients with acutely (<72 h) ruptured cerebral aneurysms treated either endovascularly or surgically.
Cerebral perfusion ...was measured both before and 1 week after treatment by use of a (99m)Tc-labeled ethyl-cysteine dimer and single-photon emission computed tomographic (SPECT) studies in 46 of 81 consecutive patients included in a prospective randomized study of early treatment of ruptured aneurysms. In addition to visual analysis of the SPECT images, corticocerebellar perfusion ratios were calculated for seven predefined bilateral regions. Late ischemic deficits were evaluated after 12 months by magnetic resonance imaging of the brain.
Acute perfusion deficits were commonly seen before treatment. In the visual comparison between the first and second SPECT studies, the number of new or enlarged deficits (P = 0.006) and deficits that expanded from unilateral to bilateral (P = 0.020) significantly increased in the surgical group but not in the endovascular group. In the second SPECT study, surgical patients had decreased corticocerebellar perfusion ratios in the right frontobasal cortex (P = 0.012) compared with the endovascular patients, and in the ipsilateral frontobasal cortex (P = 0.002) and ipsilateral temporal apex (P = 0.002) compared with the contralateral side of the ruptured aneurysm. The 12-month magnetic resonance imaging of the brain revealed no significant difference in the number of ischemic deficits between the endovascular and surgical groups.
Disturbances in cerebral perfusion both before and after treatment are common. Although no major differences in the findings were detected between patients treated with either clips or coils, progression of perfusion deficits was more common in the surgical group. However, the 12-month magnetic resonance imaging of the brain revealed equal numbers of ischemic deficits in the treatment groups.
Musical competence may confer cognitive advantages that extend beyond processing of familiar musical sounds. Behavioural evidence indicates a general enhancement of both working memory and attention ...in musicians. It is possible that musicians, due to their training, are better able to maintain focus on task-relevant stimuli, a skill which is crucial to working memory. We measured the blood oxygenation-level dependent (BOLD) activation signal in musicians and non-musicians during working memory of musical sounds to determine the relation among performance, musical competence and generally enhanced cognition. All participants easily distinguished the stimuli. We tested the hypothesis that musicians nonetheless would perform better, and that differential brain activity would mainly be present in cortical areas involved in cognitive control such as the lateral prefrontal cortex. The musicians performed better as reflected in reaction times and error rates. Musicians also had larger BOLD responses than non-musicians in neuronal networks that sustain attention and cognitive control, including regions of the lateral prefrontal cortex, lateral parietal cortex, insula, and putamen in the right hemisphere, and bilaterally in the posterior dorsal prefrontal cortex and anterior cingulate gyrus. The relationship between the task performance and the magnitude of the BOLD response was more positive in musicians than in non-musicians, particularly during the most difficult working memory task. The results confirm previous findings that neural activity increases during enhanced working memory performance. The results also suggest that superior working memory task performance in musicians rely on an enhanced ability to exert sustained cognitive control. This cognitive benefit in musicians may be a consequence of focused musical training.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A large collaborative analysis of data from 47 epidemiological studies concluded that longer duration of breastfeeding reduces the risk of developing breast cancer. Despite the strong epidemiological ...evidence, the molecular mechanisms linking prolonged breastfeeding to decreased risk of breast cancer remain poorly understood.
We modeled two types of breastfeeding behaviors in wild type FVB/N mice: (1) normal or gradual involution of breast tissue following prolonged breastfeeding and (2) forced or abrupt involution following short-term breastfeeding. To accomplish this, pups were gradually weaned between 28 and 31 days (gradual involution) or abruptly at 7 days postpartum (abrupt involution). Mammary glands were examined for histological changes, proliferation, and inflammatory markers by immunohistochemistry. Fluorescence-activated cell sorting was used to quantify mammary epithelial subpopulations. Gene set enrichment analysis was used to analyze gene expression data from mouse mammary luminal progenitor cells. Similar analysis was done using gene expression data generated from human breast samples obtained from parous women enrolled on a tissue collection study, OSU-2011C0094, and were undergoing reduction mammoplasty without history of breast cancer.
Mammary glands from mice that underwent abrupt involution exhibited denser stroma, altered collagen composition, higher inflammation and proliferation, increased estrogen receptor α and progesterone receptor expression compared to those that underwent gradual involution. Importantly, when aged to 4 months postpartum, mice that were in the abrupt involution cohort developed ductal hyperplasia and squamous metaplasia. Abrupt involution also resulted in a significant expansion of the luminal progenitor cell compartment associated with enrichment of Notch and estrogen signaling pathway genes. Breast tissues obtained from healthy women who breastfed for < 6 months vs ≥ 6 months showed significant enrichment of Notch signaling pathway genes, along with a trend for enrichment for luminal progenitor gene signature similar to what is observed in BRCA1 mutation carriers and basal-like breast tumors.
We report here for the first time that forced or abrupt involution of the mammary glands following pregnancy and lack of breastfeeding results in expansion of luminal progenitor cells, higher inflammation, proliferation, and ductal hyperplasia, a known risk factor for developing breast cancer.
Advanced glycation end products (AGEs) are reactive metabolites intrinsically linked with modern dietary patterns. Processed foods, and those high in sugar, protein and fat, often contain high levels ...of AGEs. Increased AGE levels are associated with increased breast cancer risk, however their significance has been largely overlooked due to a lack of direct cause-and-effect relationship.
To address this knowledge gap, FVB/n mice were fed regular, low AGE, and high AGE diets from 3 weeks of age and mammary glands harvested during puberty (7 weeks) or adulthood (12 weeks and 7 months) to determine the effects upon mammary gland development. At endpoint mammary glands were harvested and assessed histologically (n ≥ 4). Immunohistochemistry and immunofluorescence were used to assess cellular proliferation and stromal fibroblast and macrophage recruitment. The Kruskal-Wallis test were used to compare continuous outcomes among groups. Mammary epithelial cell migration and invasion in response to AGE-mediated fibroblast activation was determined in two-compartment co-culture models. In vitro experiments were performed in triplicate. The nonparametric Wilcoxon rank sum test was used to compare differences between groups.
Histological analysis revealed the high AGE diet delayed ductal elongation, increased primary branching, as well as increased terminal end bud number and size. The high AGE diet also led to increased recruitment and proliferation of stromal cells to abnormal structures that persisted into adulthood. Atypical hyperplasia was observed in the high AGE fed mice. Ex vivo fibroblasts from mice fed dietary-AGEs retain an activated phenotype and promoted epithelial migration and invasion of non-transformed immortalized and tumor-derived mammary epithelial cells. Mechanistically, we found that the receptor for AGE (RAGE) is required for AGE-mediated increases in epithelial cell migration and invasion.
We observed a disruption in mammary gland development when mice were fed a diet high in AGEs. Further, both epithelial and stromal cell populations were impacted by the high AGE diet in the mammary gland. Educational, interventional, and pharmacological strategies to reduce AGEs associated with diet may be viewed as novel disease preventive and/or therapeutic initiatives during puberty.
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