A5081852175- Endoplasmic Reticulum Stress and Disease
- Prostate Cancer Diagnosis and Treatment
- Prostate Cancer Treatment and Research
- Autophagy in Disease and Therapy
- Estrogen and related hormone effects
- Cytokine Signaling Pathways and Interactions
- Advanced Radiotherapy Techniques
- HER2/EGFR in Cancer Research
- Cancer, Lipids, and Metabolism
- MicroRNA in disease regulation
- Lung Cancer Treatments and Mutations
- Hormonal and reproductive studies
- Bioinformatics and Genomic Networks
- interferon and immune responses
- Cancer Research and Treatments
- Cancer-related molecular mechanisms research
- Photosynthetic Processes and Mechanisms
- Nuclear Receptors and Signaling
- RNA regulation and disease
- Mitochondrial Function and Pathology
- Pancreatic function and diabetes
- Sexual function and dysfunction studies
- Ferroptosis and cancer prognosis
- RNA Research and Splicing
- Ubiquitin and proteasome pathways
Georgetown University
2016-2025
MedStar Georgetown University Hospital
2021-2025
Georgetown University Medical Center
2010-2025
Beth Israel Deaconess Medical Center
2024
University of Pennsylvania
2024
North Carolina Central University
2022-2024
Harvard University
2024
Vince Lombardi Cancer Clinic
2005-2023
Health Sciences Centre
2022
Sunnybrook Health Science Centre
2022
Estrogen receptor-α (ERα)-targeted therapies including tamoxifen (TAM) or Faslodex (ICI) are used to treat ER(+) breast cancers. Up 50% of tumors will acquire resistance these interventions. Autophagy has been implicated as a major driver antiestrogen resistance. We have explored the ability hydroxychloroquine (HCQ), which inhibits autophagy, affect responsiveness.TAM-resistant MCF7-RR and ICI-resistant/TAM cross-resistant LCC9 cancer cells were injected into mammary fat pads female athymic...
Human X-box binding protein-1 (XBP1) is an alternatively spliced transcription factor that participates in the unfolded protein response (UPR), a stress-signaling pathway allows cells to survive accumulation of proteins endoplasmic reticulum lumen. We have previously demonstrated XBP1 expression increased antiestrogen-resistant breast cancer cell lines and coexpressed with estrogen receptor alpha (ER) tumors. The purpose this study investigate role UPR antiestrogen responsiveness cancer....
The unfolded protein response is an endoplasmic reticulum stress pathway mediated by the chaperone glucose regulated-protein 78 (GRP78). Metabolic analysis of breast cancer cells shows that GRP78 silencing increases intracellular concentrations essential polyunsaturated fats, including linoleic acid. Accumulation fatty acids due to inhibition mitochondrial acid transport, resulting in a reduction oxidation. These data suggest novel role GRP78-mediating cellular metabolism. We validated...
We have directly assessed the ability of interferon regulatory factor-1 (IRF-1) to act as a tumor suppressor gene in human breast cancer cells and explored whether this function is mechanistically conferred by affecting cell cycle transition, apoptosis and/or caspase activation. used dual approach, measuring overexpression wild-type IRF-1 or dominant negative (dnIRF-1) produce opposing effects on proliferation vitro tumorigenicity athymic nude mice. Mechanistic studies determined blocking...
Abstract One-third of all estrogen receptor (ER)–positive breast tumors treated with endocrine therapy fail to respond, and the remainder is likely relapse in future. Almost data on resistance has been obtained models invasive ductal carcinoma (IDC). However, lobular carcinomas (ILC) comprise up 15% newly diagnosed cancers each year and, whereas incidence IDC remained relatively constant during last 20 years, prevalence ILC continues increase among postmenopausal women. We report a new model...
Antiestrogen therapy induces the unfolded protein response (UPR) in estrogen receptor-positive (ER(+)) breast cancer. X-box binding 1 (XBP1), which exists transcriptionally inactive unspliced form [XBP1(U)] and spliced active [XBP1(S)], is a key UPR component mediating antiestrogen resistance. We now show direct link between XBP1 NF-κB survival pathways driving cell fate decisions to antiestrogens ER(+) cancer cells, both vitro xenograft mouse model. Using novel nonspliceable forms of XBP1,...
Resistance to endocrine therapies remains a major problem in the management of estrogen receptor-alpha (ER)-positive breast cancer. We show that inhibition NF-kappaB (p65/RELA), either by overexpression mutant IkappaB (IkappaBSR) or small-molecule inhibitor (parthenolide; IC(50)=500 nM tamoxifen-resistant cells), synergistically restores sensitivity 4-hydroxytamoxifen (4HT) resistant MCF7/RR and MCF7/LCC9 cells further sensitizes MCF-7 MCF7/LCC1 control 4HT. These effects are independent...
Abstract Antiestrogens are effective therapies for the management of many estrogen receptor-α (ER)–positive breast cancers. Nonetheless, both de novo and acquired resistance occur remain major problems in clinical setting. IFNγ is an inflammatory cytokine that induces expression function IFN regulatory factor 1 (IRF1), a tumor suppressor gene can increase antiestrogen responsiveness. We show IFNγ, but not IFNα, IFNβ, or fulvestrant (ICI; ICI 182,780; Faslodex), IRF1 antiestrogen-resistant...
Immune checkpoint inhibitors, including PD-L1/PD-1, are key regulators of the immune response and promising targets in cancer immunotherapy. N-glycosylation PD-L1 affects its interaction with PD-1, but little is known about distribution glycoforms at four NXS/T sequons. We optimized LC–MS/MS methods using collision energy modulation for site-specific resolution specific glycan motifs. demonstrate that on surface breast cell line carries mostly complex glycans a high proportion polyLacNAc...
Studies have demonstrated that injectable GnRH receptor agonists further suppress cancer progression when paired with radiotherapy (RT) in patients intermediate- to high-risk prostate adenocarcinoma. Relugolix is a newly available oral antagonist achieves swift and profound castration (total testosterone <20 ng/dl) at high rates, which may shape patients' health-related quality of life. The main objective this prospective study was explore the effects neoadjuvant relugolix on life...
Introduction Injectable GnRH receptor agonists have been shown to improve cancer control when combined with radiotherapy (RT). Relugolix is an oral antagonist that achieves rapid testosterone suppression. Non-adherence medications due poor social support or bothersome side effects may increase the risk of recurrence. This prospective study sought evaluate early suppression and relugolix drug adherence prostate stereotactic body radiation therapy (SBRT). Utilization patient-reported outcomes...
BCL2 family members affect cell fate decisions in breast cancer but the role of BCL-W (BCL2L2) is unknown. We now show integrated roles antiapoptotic and affecting responsiveness to antiestrogen ICI 182,780 (ICI; Fulvestrant Faslodex), using both molecular (siRNA; shRNA) pharmacologic (YC137) approaches three variants; MCF-7/LCC1 (ICI sensitive), MCF-7/LCC9 resistant), LY2 resistant). YC137 inhibits restores sensitivity resistant cells. Co-inhibition necessary sufficient restore ICI,...
Lack of understanding endocrine resistance remains one the major challenges for breast cancer researchers, clinicians, and patients. Current reductionist approaches to molecular signaling driving have offered mostly incremental progress over past 10 years. As field systems biology has begun mature, network modeling tools being developed applied therein offer a different way think about how regulation critical cellular functions are integrated. To gain novel insights, we first describe some...
The postnatal mammary gland undergoes repeated cycles of proliferation and cell death, most notably when the fully differentiated (lactating) dedifferentiates to a prelactation state. Accumulation milk proteins in secretory epithelium creates stress signal that triggers this process (involution). How is perceived, cellular processes are subsequently activated, remain unclear. We now report Unfolded Protein Response (UPR), autophagy, apoptosis related genes cluster separately during lactation...
Phosphatase and tensin homolog (PTEN) genomic deletions transmembrane protease, serine 2/v-ets avian erthyroblastosis virus E26 oncogene (ERG) rearrangements are two of the most common genetic abnormalities associated with prostate cancer. Prior studies have demonstrated these alterations portend worse clinical outcomes. Our objective is to evaluate impact biopsy-determined PTEN losses TMPRSS2-ERG fusion on biochemical progression-free survival (bPFS) overall (OS) in patients who receive...
Established human breast cancer cell lines are widely used as experimental models in research. While these and their variants share many phenotypic characteristics with tumors, the extent to which they reflect underlying molecular biology of remains controversial. We explored this issue using a probabilistic rather than heuristic approach. Data from gene expression microarrays were compare global structures transcriptomes three estrogen receptor alpha positive (ER+) (MCF-7, T47D, ZR-75-1) 13...
Responses to endocrine therapies vary among patients with estrogen receptor (ER+) breast cancer. We studied whether in utero exposure endocrine-disrupting compounds might explain these variations.We describe a novel ER+ cancer model study de novo and acquired tamoxifen (TAM) resistance. Pregnant Sprague Dawley rats were exposed 0 or 0.1 ppm ethinyl estradiol (EE2), the response of 9,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors 15 mg/kg TAM, (n = 17 controls n 20 EE2 offspring)...
Invasive lobular breast cancer (ILC) is an understudied malignancy with distinct clinical, pathological, and molecular features that distinguish it from the more common invasive ductal carcinoma (IDC). Mounting evidence suggests estrogen receptor-alpha positive (ER+) ILC has a poor response to Tamoxifen (TAM), but mechanistic drivers of this are undefined. In current work, we comprehensively characterize SUM44/LCCTam cell model system through integrated analysis gene expression, copy number,...
Introduction Sexual function following local treatment for prostate cancer is an important quality of life concern. Relugolix a novel oral GnRH receptor antagonist used in combination with radiation therapy the unfavorable cancer. It has been shown to achieve rapid and profound testosterone suppression. As result, these very low levels may impact both sexual functioning perceptions. This prospective study sought assess neoadjuvant relugolix-induced dysfunction prior stereotactic body (SBRT)....
Abstract The molecular mechanisms underlying the acquisition of resistance to antiestrogen Faslodex are poorly understood, although enhanced expression and activity nuclear factor κB (NFκB) have been implicated as a critical element this phenotype. purpose study was elucidate mechanism by which NFκB up-regulation contributes determine whether pharmacologic inhibition small molecule parthenolide could restore Faslodex-mediated suppression cell growth. Basal multiple NFκB-related molecules in...
Abstract In rats, prepubertal exposure to low-fat diet containing n-3 polyunsaturated fatty acids (PUFA) reduces mammary cell proliferation, increases apoptosis, and lowers risk of tumors in adulthood, whereas high-fat PUFA has opposite effects. To identify signaling pathways mediating these effects, we performed gene microarray analyses determined protein levels genes related epithelial proliferation. Nursing female rats rat pups were fed (16% energy from fat) or (39% n-6 diets between...