Breast Cancer
6/12(2008)
. Int J Oncol. 2008
Mar;32(3):593-601. Zhao
L, Yano
T, Osuga Y, Nakagawa
S, Oishi H, Wada-Hiraike O, Tang
X, Yano
N, Kugu K, Schally AV, Taketani Y. Department of Obstetrics and
Gynecology, Faculty of Medicine, The The expression of growth
hormone-releasing hormone (GHRH) and its receptors has been demonstrated in
peripheral tissues as well as CNS. Recently, the functional splice variant
SV1 of GHRH receptor was identified in various human cancers and cancer
cell lines. Although antineoplastic activity of
GHRH antagonists has been clearly demonstrated, the mechanism of action is
incompletely understood. The objective of this study was the investigation
of direct anti-proliferative effect of GHRH
antagonist MZ-5-156 on HEC-1A human endometrial cancer cell line and the
elucidation of underlying mechanisms. RT-PCR revealed the expression of
mRNA for GHRH and SV1 of GHRH receptor in HEC-1A cells. MZ-5-156, at
concentrations between 10(-7) and 10(-5) M, had a dose-dependent antiproliferative effect on HEC-1A cells, as determined
by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,
(MTS) assay. Hoechst 33342 staining and flow cytometric
analysis indicated that MZ-5-156, at 10(-6) M, induced apoptosis in HEC-1A
cells after 48 h of treatment. Western blot analysis of apoptosis-related
proteins demonstrated that treatment with MZ-5-156 (10(-6) M) for 48 h
significantly increased the protein levels of Fas,
phospho-p53 (Ser46), p53AIP1 (p53-regulated Apoptosis-Inducing Protein 1),
and caspase-8, -9, and -3, and decreased the protein level of Bcl-2. These
results demonstrate that MZ-5-156 can directly inhibit the proliferation of
human endometrial cancer cells, which express mRNA for GHRH and SV1 of GHRH
receptor, presumably through the induction of p53-dependent apoptosis
coupled with the up-regulation of Fas,
phospho-p53 (Ser46), p53AIP1, and caspase-8, -9, and -3, and the
down-regulation of Bcl-2. PMID: 18292936 [PubMed
- indexed for MEDLINE] Breast
Cancer Res. 2008;10(2):R30. Epub 2008 Apr 1. von
Minckwitz G, Sinn
HP, Raab G, Loibl S, Blohmer JU, Eidtmann H, Hilfrich J, Merkle E, Jackisch C, Costa
SD, Caputo
A, Kaufmann
M; German
Breast Group. Dept. of
Gynecology and Obstetrics, INTRODUCTION: To investigate the
predictive value of clinical and biological markers for a pathological
complete remission after a preoperative dose-dense regimen of doxorubicin
and docetaxel, with or without tamoxifen, in primary operable breast cancer. METHODS:
Patients with a histologically confirmed
diagnosis of previously untreated, operable, and measurable primary breast
cancer (tumour (T), nodes (N) and metastases (M)
score: T2-3(> or = 3 cm) N0-2 M0) were treated in a prospectively randomised trial with four cycles of dose-dense
(bi-weekly) doxorubicin and docetaxel (ddAT) chemotherapy, with or without tamoxifen,
prior to surgery. Clinical and pathological parameters (menopausal status,
clinical tumour size and nodal status, grade, and
clinical response after two cycles) and a panel of biomarkers (oestrogen and progesterone receptors, Ki-67, human
epidermal growth factor receptor 2 (HER2), p53, bcl-2, all detected by immunohistochemistry) were correlated with the
detection of a pathological complete response (pCR).
RESULTS: A pCR was observed in 9.7% in 248
patients randomised in the study and in 8.6% in
the subset of 196 patients with available tumour
tissue. Clinically negative axillary lymph nodes,
poor tumour differentiation, negative oestrogen receptor status, negative progesterone
receptor status, and loss of bcl-2 were significantly predictive for a pCR in a univariate logistic
regression model, whereas in a multivariate analysis only the clinical
nodal status and hormonal receptor status provided significantly
independent information. Backward stepwise logistic regression revealed a
response after two cycles, with hormone receptor status and lymph-node
status as significant predictors. Patients with a low percentage of cells
stained positive for Ki-67 showed a better response when treated with tamoxifen, whereas patients with a high percentage of
Ki-67 positive cells did not have an additional benefit when treated with tamoxifen. Tumours overexpressing HER2 showed a similar response to that
in HER2-negative patients when treated without tamoxifen,
but when HER2-positive tumours were treated with tamoxifen, no pCR was
observed. CONCLUSION: Reliable prediction of a pathological complete
response after preoperative chemotherapy is not possible with clinical and
biological factors routinely determined before start of treatment. The
response after two cycles of chemotherapy is a strong but dependent
predictor. The only independent factor in this subset of patients was
bcl-2. PMID: 18380893 [PubMed
- in process] Mol Endocrinol.
2004 Jun;18(6):1471-85. Epub
2004 Mar 25. Huang
Y, Kim
SO, Yang
N, Jiang J, Frank
SJ. Department
of Medicine, GH and IGF-I are critical
regulators of growth and metabolism. GH interacts with the GH receptor
(GHR), a cytokine superfamily receptor, to
activate the cytoplasmic tyrosine kinase, Janus kinase 2 (JAK2), and initiate intracellular signaling
cascades. IGF-I, produced in part in response to GH, binds to the heterotetrameric IGF-I receptor (IGF-IR), which is an
intrinsic tyrosine kinase growth factor receptor
that triggers proliferation, antiapoptosis, and
other biological actions. Previous in vitro and overexpression
studies have suggested that JAKs may interact
with IGF-IR and that IGF-I stimulation may activate JAKs.
In this study, we explore interactions between GHR-JAK2 and IGF-IR
signaling pathway elements utilizing the GH and IGF-I-responsive 3T3-F442A
and 3T3-L1 preadipocyte cell lines, which
endogenously express both the GHR and IGF-IR. We find that GH induces
formation of a complex that includes GHR, JAK2, and IGF-IR in these preadipocytes. The assembly of this complex in intact
cells is rapid, GH concentration dependent, and can be prevented by a GH
antagonist, G120K. However, it is not inhibited by the kinase
inhibitor, staurosporine, which markedly inhibits
GHR tyrosine phosphorylation. Moreover, complex
formation does not appear dependent on GH-induced activation of the ERK or phosphatidylinositol 3-kinase signaling pathways or on
the tyrosine phosphorylation of GHR, JAK2, or
IGF-IR. These results suggest that GH-induced formation of the
GHR-JAK2-IGF-IR complex is governed instead by GH-dependent conformational
change(s) in the GHR and/or JAK2. We further demonstrate that GH and IGF-I
can synergize in acute aspects of signaling and that IGF-I enhances
GH-induced assembly of conformationally active GHRs. These findings suggest the existence of
previously unappreciated relationships between these two hormones. PMID: 15044591 [PubMed
- indexed for MEDLINE]
Cellular mechanisms of growth inhibition of
human endometrial cancer cell line by an antagonist of growth
hormone-releasing hormone.
Clinical response after two cycles compared to
HER2, Ki-67, p53, and bcl-2 in independently predicting a pathological
complete response after preoperative chemotherapy in patients with operable
carcinoma of the breast.
Physical and functional
interaction of growth hormone and insulin-like growth factor-I signaling
elements.