8 research outputs found
MMTV-PyMT and derived Met-1 mouse mammary tumor cells as models for studying the role of the androgen receptor in triple-negative breast cancer progression
Triple-negative breast cancer (TNBC) has a faster rate of metastasis compared to other breast cancer subtypes and no effective targeted therapies are currently FDA-approved. Recent data indicate that the androgen receptor (AR) promotes tumor survival and may serve as a potential therapeutic target in TNBC. Studies of AR in disease progression and the systemic effects of anti-androgens have been hindered by the lack of an AR-positive (AR+) immunocompetent preclinical model. In this study we identified the transgenic MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor antigen) mouse mammary gland carcinoma model of breast cancer and Met-1 cells derived from this model as tools to study the role of AR in breast cancer progression. AR protein expression was examined in late-stage primary tumors and lung metastases from MMTV-PyMT mice as well as in Met-1 cells by immunohistochemistry (IHC). Sensitivity of Met-1 cells to the AR agonist dihydrotestosterone (DHT) and anti-androgen therapy was examined using cell viability, migration/invasion, and anchorage-independent growth assays. Late-stage primary tumors and lung metastases from MMTV-PyMT mice and Met-1 cells expressed abundant nuclear AR protein, while negative for estrogen and progesterone receptors. Met-1 sensitivity to DHT and AR antagonists demonstrated a reliance on AR for survival, and AR antagonists inhibited invasion and anchorage-independent growth. These data suggest that the MMTV-PyMT model and Met-1 cells may serve as valuable tools for mechanistic studies of the role of AR in disease progression and how anti-androgens affect the tumor microenvironment
Synthesis and Evaluation of Bivalent NDP-Ī±-MSH(7) Peptide Ligands for Binding to the Human Melanocortin Receptor 4 (hMC4R)
Predictive features of ligandāspecific signaling through the estrogen receptor
Some estrogen receptorāĪ± (ERĪ±)ātargeted breast cancer therapies such as tamoxifen have tissueāselective or cellāspecific activities, while others have similar activities in different cell types. To identify biophysical determinants of cellāspecific signaling and breast cancer cell proliferation, we synthesized 241 ERĪ± ligands based on 19 chemical scaffolds, and compared ligand response using quantitative bioassays for canonical ERĪ± activities and Xāray crystallography. Ligands that regulate the dynamics and stability of the coactivatorābinding site in the Cāterminal ligandābinding domain, called activation functionā2 (AFā2), showed similar activity profiles in different cell types. Such ligands induced breast cancer cell proliferation in a manner that was predicted by the canonical recruitment of the coactivators NCOA1/2/3 and induction of the GREB1 proliferative gene. For some ligand series, a single interāatomic distance in the ligandābinding domain predicted their proliferative effects. In contrast, the Nāterminal coactivatorābinding site, activation functionā1 (AFā1), determined cellāspecific signaling induced by ligands that used alternate mechanisms to control cell proliferation. Thus, incorporating systems structural analyses with quantitative chemical biology reveals how ligands can achieve distinct allosteric signaling outcomes through ERĪ±
Tumor Targeting and Pharmacokinetics of a Near-Infrared Fluorescent-Labeled Ī“āOpioid Receptor Antagonist Agent, Dmt-Tic-Cy5
Fluorescence
molecular imaging can be employed for the development
of novel cancer targeting agents. Herein, we investigated the pharmacokinetics
(PK) and cellular uptake of Dmt-Tic-Cy5, a delta-opioid receptor (Ī“OR)
antagonistāfluorescent dye conjugate, as a tumor-targeting
molecular imaging agent. Ī“OR expression is observed normally
in the CNS, and pathologically in some tumors, including lung liver
and breast cancers. In vitro, in vivo, and ex vivo experiments were
conducted to image and quantify the fluorescence signal associated
with Dmt-Tic-Cy5 over time using in vitro and intravital fluorescence
microscopy and small animal fluorescence imaging of tumor-bearing
mice. We observed specific retention of Dmt-Tic-Cy5 in tumors with
maximum uptake in Ī“OR-expressing positive tumors at 3 h and
observable persistence for >96 h; clearance from Ī“OR nonexpressing
negative tumors by 6 h; and systemic clearance from normal organs
by 24 h. Live-cell and intravital fluorescence microscopy demonstrated
that Dmt-Tic-Cy5 had sustained cell-surface binding lasting at least
24 h with gradual internalization over the initial 6 h following administration.
Dmt-Tic-Cy5 is a Ī“OR-targeted agent that exhibits long-lasting
and specific signal in Ī“OR-expressing tumors, is rapidly cleared
from systemic circulation, and is not retained in non-Ī“OR-expressing
tissues. Hence, Dmt-Tic-Cy5 has potential as a fluorescent tumor imaging
agent