III-THE ROLE OF PROGESTERONE IN NORMAL ENDOMETRIUM AND IN ENDOMETRIAL CANCER
The endometrium is the tissue that lines the uterine cavity. It is made of a layer of columnar luminal epithelium supported by cellular stroma with tubular glands, immune cells and blood vessels.
From the onset of menarche to menopause, the endometrium undergoes extensive modification in response to the ovarian steroid hormones estrogen and progesterone during each menstrual cycle in preparation for nidation. Estrogen promotes proliferation and growth of the endometrium while progesterone antagonizes estrogen-driven growth and promotes differentiation.
Specifically, when progesterone levels are high during the ...view middle of the document...
For instance, the amount of stroma is considerably decreased in endometrial cancer compared with cycling endometrium. The stroma highly react to progesterone and dynamically influences the epithelium in a paracrine way. Without sufficient stroma, progesterone response would be affected. Accordingly, progesterone responsiveness might be dictated not only by the hyperplastic or malignant epithelium but also by the stroma. the role of stroma, in response to progesterone, in modulating glandular transformation is poorly known and it would be an area worth investigating in order to further understand the prevention or the treatment of endometrial carcinoma.
In endometrial cancer, progesterone opposes the estrogen-driven proliferation, inhibits cellular adhesion molecules, and promotes cell differentiation and apoptosis . But in the literature, mechanism of those anti-tumor effects of progesterone remain unknown . However, there are theories increasingly arising from research studies on this field [30-32].
Numerous genes and several molecular mechanisms have been implicated in the progestin-mediated responses seen in endometrial cancer cells.
The regulation of genes that include cyclin D1, MMP-1, -2, -7 and -9, and Ets-1 in response to progestins have been implicated in mediating the inhibition of cell growth and invasiveness.Primary endometrial tumor cells also respond to progestins through significantly decreasing pro-MMP-9, pro-MMP-2, and MMP-2 release.
Progestins are reported to stimulate the expression of glycodelin in Ishikawa cells, which inhibits G1/S transition of cell cycle and upregulates CDKI enzymes, consequently reducing cell spread. Overexpression of PR-A and PR-B in endometrial cancer cells resulted in a significant progesterone-dependent inhibition of cellular adhesion molecules expression such as fibronectin, integrin a3, integrin b1, integrin b3, and cadherin [35-39].
Progestins can increase FOXO1 protein levels in Ishikawa cells. That is specifically through PR-B and promotes cell cycle arrest and apoptosis in these cells. Remarkably, levels of FOXO1 protein are significantly lower in 77% or 95.9% of endometrial tumor tissues compared with normal endometrial tissues [40, 41].
There were microarray studies which showed that short-term (4 hour) and high-dose (~30 µg/ml) exposure of Ishikawa cells to progesterone resulted in 247 differentially expressed genes, of which 135 genes were involved in biological processes like cell cycle, cell proliferation and differentiation, developmental processes, immune responses, and intracellular protein traffic and transport.
Other microarray studies where endometrial cancer cells transfected with PR were treated with progestins for 12h.The result showed that progestins inhibited genes related to metastasis and significantly regulated genes associated with cell signaling, DNA remodeling, apoptosis, tumor suppressor, and transcription factors. Interestingly, there was...