Is the estrogen-dependency of NF tumors' growth a "myth" or the "truth"?

http://www.paternityangel.com/Articles_zone/Hormones/Hormones3.htm

During the pregnancy, estrogen level rises, and as a consequence progesterone level also goes up, to assist the embyos develop fully in the womb of mothers. Interestingly, many women with NF (neurofibromatosis), both NF1 and NF2, are widely known to experience that their NF tumors start growing faster shortly after their pregnancy. In fact, generally speaking, the severity of both NF1 and NF2 among women appears to be greater than that among men, although the frequency of NF per se is independent of gender (one out of around 3,000).

Thus, a question has arisen whether estrogen or progesterone stimulates the growth of these NF tumors. The majority of NF clinicians tend to dismiss the potential effect of these steroid hormones on NF tumors, saying so far there is no experimental evidence supporting this myth. Is this really just a myth or feeling of NF mothers?

My own opinion would be that at least estrogen stimulate the growth of both NF1 and NF2 tumors, although the effect of progestrone still remains uncertain until recently. I will tell you why. First of all, we found that the growth of both NF1 and NF2 tumors require the kinase called PAK1. This kinase is activated by estrogen receptor (ER) in breast and cervical cancers, and in turn PAK1 reactivates ER, keeping a vicious oncogenic cycle. The growth of these female cancers also requires PAK1, clearly indicating that the oncogenic role of ER-PAK1 signaling in these cancers. How about in NF tumors?

Last November a group led by George Perrin in Florida finally showed that MPNST, NF1 cancer, xenograft in mice grows far more slowly when ovary is removed from mice to block the production of both estrogen and progesterone. Furthermore, replacement of either estrogen or progesterone alone restores the fast growth of MPNST in mice, clearly indicating that both of these steroid hormones have a positive effect on the growth of MPNST. Thus, it is likely that these hormones affect similarly the growth of NF2 tumor, too.

In short, I am now quite convinced that both hormones play a significant role in speeding up the growth of both NF1 and NF2 tumors during the pregnancy, although how progesterone stimulates their growth still remains in mystery at molecular levels.

In cervical cancers where the tumor suppressor PTEN frequently dysfunctions, both kinases PAK1 and AKT are abnormally activated. There the tumor suppressor FOXO is down-regulated. Interestingly it was found very recently by a group in Chicago that progestins, antagonists of progesterone, up-regulate FOXO and suppress the growth of these cancers. In other words, like estrogen, progesterone also down-regulates the FOXO, thereby stimulating the cancer growth.

As described before, FOXO is required for the longevity. Thus, it is likely that the pregnancy would not only stimulate the growth of a variety of PAK1-dependent tumors, but also shorten the life span of women. In a tiny nematode called C.elegans, we have clearly seen that PAK1-deficiency reduces significantly the number of eggs this worm lays, and somehow up-regulates FOXO which would prolong its life span, suggesting that the lower their reproduction, the longer their life-span. This outcome appears to make sense, at least in terms of the survival of each family.

Regarding human beings, why can women live longer than men? Androgen receptor (AR) directly inhibits the function of FOXO in prostate cancers. Is androgen more effective than estrogen/progesterone to shorten our life span by inactivating FOXO? Probably only God knows.

To be continued