3 research outputs found
Progesterone receptors in development and metatstais of endometrial cancer
Many women may acquire endometrial cancer during their life. The vast majority of
these women will be cured because of early detection of the disease. As in most
types of cancer however, the main cause of death lies in metastasis of the primary
tumor to other sites in the body. In approximately 25% of endometrial cancer
patients, the tumor has spread beyond the uterus at the time of initial surgical
treatment.
During endometrial carcinogenesis, the balance between estrogen and
progesterone is of great importance. This is indicated by the fact that virtually all risk
factors for endometrial cancer are linked to a surplus of estrogenic effects that are
not balanced by appropriate progestagenic effects. Also during further development
and progression of endometrial cancer, steroid receptor signaling has many
important effects.
The major research question of this thesis is summarized as follows: what is the
effect of loss of progesterone regulation due to loss of PR expression during
development of endometrial cancer? More specifically, the questions that this thesis
addresses are:
1) Is loss of PR expression in endometrial cancer linked to development of
endometrial cancer to a more advanced stage?
2) What are the effects of changes in expression of PRA and PRB on invasion
and metastasis of endometrial cancer?
3) What is the effect of progesterone on invasion and metastasis of endometrial
cancer cells that express different PR isotypes?
4) Does any crosstalk exist between PR signaling and Wnt signaling
Progestogenic effects of tibolone on human endometrial cancer cells
Tibolone, a synthetic steroid acting in a tissue-specific manner and used
in hormone replacement therapy, is converted into three active
metabolites: a Delta(4) isomer (exerting progestogenic and androgenic
effects) and two hydroxy metabolites, 3 alpha-hydroxytibolone (3
alpha-OH-tibolone) and 3beta-OH-tibolone (exerting estrogenic effects). In
the present study an endometrial carcinoma cell line (Ishikawa PRAB-36)
was used to investigate the progestogenic properties of tibolone and its
metabolites. This cell line contains progesterone receptors A and B, but
lacks estrogen and androgen receptors. When tibolone was added to the
cells, complete conversion into the progestogenic/androgenic Delta(4)
isomer was observed within 6 d. Furthermore, when cells were cultured with
tibolone or when the Delta(4) isomer or the established progestagen
medroxyprogesterone acetate was added to the medium, marked inhibition of
growth was observed. Interestingly, 3 beta-OH-tibolone also induces some
inhibition of growth. These growth inhibitions were not observed in
progesterone receptor-negative parental Ishikawa cells, and
progestagen-induced growth inhibition of PRAB-36 cells could readily be
reversed using the antiprogestagen Org-31489. Upon measuring the
expression of two progesterone-regulated genes (fibronectin and
IGF-binding protein-3), tibolone, the Delta(4) isomer and
medroxyprogesterone acetate showed similar gene expression regulation.
These results indicate that tibolone, the Delta(4) metabolite, and to some
extent 3 beta-OH-tibolone exert progestogenic effects. Tibolone and most
likely 3 beta-OH-tibolone are converted into the Delta(4) metabolite
Consequences of loss of progesterone receptor expression in development of invasive endometrial cancer
PURPOSE: In endometrial cancer, loss of progesterone receptors (PR) is
associated with more advanced disease. This study aimed to investigate the
mechanism of action of progesterone and the loss of its receptors (PRA and
PRB) in development of endometrial cancer. EXPERIMENTAL DESIGN: A
9600-cDNA microarray analysis was performed to study regulation of gene
expression in the human endometrial cancer subcell line Ishikawa PRAB-36
by the progestagen medroxy progesterone acetate (MPA). Five MPA-regulated
genes were selected for additional investigation. Expression of these
genes was studied by Northern blot and by immunohistochemistry in Ishikawa
subcell lines expressing different PR isoforms. Additionally, endometrial
cancer tissue samples were immunohistochemically stained to study the in
vivo protein expression of the selected genes. RESULTS: In the PRAB-36
cell line, MPA was found to regulate the expression of a number of
invasion- and metastasis-related genes. On additional investigation of
five of these genes (CD44, CSPG/Versican, Tenascin-C, Fibronectin-1, and
Integrin-beta 1), it was observed that expression and progesterone
regulation of expression of these genes varied in subcell lines expressing
different PR isoforms. Furthermore, in advanced endometrial cancer, it was
shown that loss of expression of both PR and E-cadherin was associated
with increased expression CD44 and CSPG/Versican. CONCLUSION: The present
study shows that progestagens exert a modulatory effect on the expression
of genes involved in tumor cell invasion. As a consequence, loss of PR
expression in human endometrial cancer may lead to development of a more
invasive phenotype of the respective tumor