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Principal Investigator: Zhenkun Lou
Organization: MAYO CLINIC ROCHESTER
Fiscal Year: 2024
Award: $345,528
Funding agency: National Cancer Institute
Triple negative breast cancer (TNBC) [estrogen receptor (ER), progesterone receptor (PR), and human
epidermal growth factor receptor 2 (HER2) negative breast cancer is an aggressive subtype of breast cancer
for which there are no approved targeted therapies. While standard chemotherapy reduces the risk of a
disease event, patients with residual TNBC after neoadjuvant chemotherapy have a high risk of locoregional
recurrence despite surgical resection and aggressive postoperative radiotherapy. Therefore, better
understanding mechanisms of TNBC progression and identifying novel treatment approaches for
patients who have progressed on standard treatment are of great needs. PD-L1 is overexpressed in
TNBC, relative to normal breast tissue and other breast cancer subtypes. Aberrant PD-L1 expression on
tumors is an important means of evading elimination by its host immune system. The binding of programmed
death ligand 1 (PD-L1) to its receptor, programmed cell death protein 1 (PD-1) transmits signals that inhibit T-
cell activation. Therefore, abrogating the PD-1/PD-L1 interaction with therapeutic antibodies has been explored
as a means to enhance antitumor immunity. Although the extracellular role of PD-L1 in the regulation of T-cell
responses has been well studied, potential intracellular functions of PD-L1 in cancer remain largely
unknown. Surprisingly, we have found that TNBC proliferation requires PD-L1 and a subset of PD-L1 localizes
in the nucleus and interacts with cohesin, a protein complex that is important for appropriate chromosome
alignment and segregation during the cell cycle. Our Preliminary Data suggest that PD-L1 directly regulates
cohesion function in TNBC. Knocking down PD-L1 dramatically causes incomplete chromosome segregation
and inhibits TNBC cell proliferation, while has no effect on normal cells. The central hypothesis being tested
in this proposal is that PD-L1 regulates cell cycle and chromosomal stability in triple negative breast
cancer (TNBC), and targeting the intracellular/nuclear function of PD-L1 or pathways (mitosis and
cohesin) regulated by PD-L1 is of therapeutic use. We propose to test this central hypothesis in the
following Specific Aims: Aim 1, Determine the role of PD-L1 in regulation of cell cycle, genomic stability, and
tumor cell proliferation by studying the exact mechanisms by which nuclear PD-L1 might regulate cohesion.
Aim 2, Study the regulation of PD-L1 during cell cycle and mitosis. Aim 3, Evaluate the inhibition of PD-L1
nuclear function on chromosome segregation, tumor growth and response to radiochemotherapy both in vitro
and in animal models. The overall impact from the successful completion of this work will be a more complete
understanding of the role of PD-L1 in cancer pathogenesis. In addition, our work will lead to the design of more
rational and effective combination therapies for TNBC patients by defining novel strategies that not only
enhance cancer therapy by inhibiting mitosis but also unleash the antitumor activity of the patient’s immune
system.
Terms: <Abscission><Acetylation><Adjuvant Chemotherapy><Adjuvant Drug Therapy><Affect><Animal Model><Animal Models and Related Studies><Antibodies><Attention><B7-H1><B7H1><Binding><Breast Cancer><Breast Cancer Cell><Breast Cancer Patient><Breast Tissue><Breast Tumor Patient><CD274><Cancer Treatment><Cancers><Cell Communication and Signaling><Cell Cycle><Cell Cycle Control><Cell Cycle Regulation><Cell Division Cycle><Cell Growth in Number><Cell Multiplication><Cell Nucleus><Cell Proliferation><Cell Signaling><Cell division><Cellular Expansion><Cellular Growth><Cellular Proliferation><Chromosomal Stability><Chromosome Segregation><Chromosome Stabilities><Chromosomes><Clinical><Combined Modality Therapy><Data><Detectable Residual Disease><Disease><Disorder><EGF Receptor><EGFR><ERBB Protein><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Estrogen Receptors><Event><Excision><Extirpation><Genome Stability><Genomic Stability><HER1><Heterograft><Heterologous Transplantation><Human><Immune><Immune response><Immune system><Immunes><Immunological response><In Vitro><Induction Therapy><Intracellular Communication and Signaling><M Phase><Malignant Breast Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mammary Gland Parenchyma><Mammary Gland Tissue><Metabolic Glycosylation><Minimal Residual Disease><Mitosis><Mitosis Inhibition><Mitosis Stage><Modern Man><Molecular Interaction><Multimodal Therapy><Multimodal Treatment><NEOADJ><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Normal Cell><Nuclear><Nucleus><Operative Procedures><Operative Surgical Procedures><PD 1><PD-1><PD-L1><PD1><PDL-1><PDL1><Pathogenesis><Pathway interactions><Patients><Post-Operative><Postoperative><Postoperative Period><Progesterone Receptors><Progestin Receptors><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Proliferating><Proteins><Radiation therapy><Radiotherapeutics><Radiotherapy><Receptor Protein><Recurrence><Recurrent><Regulation><Removal><Residual><Residual Neoplasm><Residual Tumors><Residual state><Risk Reduction><Role><Signal Transduction><Signal Transduction Systems><Signaling><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><T cell regulation><T cell response><T-Cell Activation><TGF-alpha Receptor><TNBC><Testing><Therapeutic Uses><Therapeutic antibodies><Transforming Growth Factor alpha Receptor><Transmission><Tumor Cell><Tumor Immunity><Tumor Promotion><Urogastrone Receptor><Variant><Variation><Work><Xenograft><Xenograft procedure><Xenotransplantation><activate T cells><anti-cancer therapy><anti-tumor immunity><antitumor immunity><biological signal transduction><breast cancer progression><breast cancer survival><breast tumor cell><c-erbB-1><c-erbB-1 Protein><cancer immunity><cancer sub-types><cancer subtypes><cancer therapy><cancer-directed therapy><cell growth><chemo-/radio-therapy><chemo-radio-therapy><chemo-radiotherapy><chemoradiation><chemoradiation therapy><chemoradiation treatment><chemoradiotherapy><chemotherapy><chromosome division><cohesin><cohesion><combination therapy><combined modality treatment><combined treatment><design><designing><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><extracellular><glycosylation><high risk><host response><hypoimmunity><immune deficiency><immune system response><immunodeficiency><immunoresponse><induction therapies><irradiation response><knock-down><knockdown><malignancy><malignant breast tumor><model of animal><mouse model><multi-modal therapy><multi-modal treatment><murine model><neoplasm/cancer><neoplastic cell><new approaches><novel><novel approaches><novel strategies><novel strategy><overexpress><overexpression><pathway><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><protein complex><protein death-ligand 1><proto-oncogene protein c-erbB-1><radiation response><radiation treatment><radio-chemo-therapy><radio-chemotherapy><radiochemotherapy><receptor><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><resection><residual disease><response><response to radiation><response to therapy><response to treatment><risk-reducing><segregation><sle2><social role><standard care><standard treatment><surgery><systemic lupus erythematosus susceptibility 2><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic response><therapy response><transmission process><treatment response><treatment responsiveness><treatment with radiation><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor growth><xeno-transplant><xeno-transplantation>