Menin -today's growth promoter, tomorrow's tumor suppressor

Elucidating the Role of Menin During Islet Cell Development in the Human Fetal Pancreas
-Dubrick, Jessica L., (2013).  
University of Western Ontario - Electronic Thesis and Dissertation Repository. Paper 1287.
http://ir.lib.uwo.ca/etd/1287

editor's notes:

Menin functions as a tumor suppressor in adult endocrine cells, but in the fetal pancreas promotes cell survival and proliferation.  At first glance these roles seem very different, almost opposite.  But are they really opposed?

If menin promotes the proliferation of healthy pancreas cells -in particular, cells with at least one functional MEN1 gene- then it would seem that these cells will proliferate faster than those unable to produce menin.  So, cells that are unable to produce menin will represent a decreasing fraction of the cell population. Therefore, even during fetal development, menin's role as a growth promoter offers a tumor suppressive advantage to the developing pancreas, by reducing the percentage of cells that later may pose a tumorigenic risk due to their inability to express menin.

Unless I've got that wrong.

MEN1 -overview and treatment

Multiple endocrine neoplasia type 1 (MEN1)
-Richard W. Carroll
Asia-Pacific Journal of Clinical Oncology,Wiley Online Library, 2012
doi: 10.1111/ajco.12046

Genetic and Clinical Features of Multiple Endocrine Neoplasia Types 1 and 2

Genetic and Clinical Features of Multiple Endocrine Neoplasia Types 1 and 2

-C. Romei, et al.
Journal of Oncology, Volume 2012, Article ID 705036

MEN1 intragenic deletions appear common in sporadic primary hyperparathyroidism

MEN1 intragenic deletions may represent the most prevalent somatic event in sporadic primary hyperparathyroidism

-M Alvelos, et al.
European Journal of Endocrinology, October 23, 2012 EJE-12-0327

Vitamin D and cancer

Vitamin D and cancer
-Vuolo L, Di Somma C, Faggiano A and Colao A (2012) Vitamin D and cancer.
Front. Endocrin. 3:58. doi: 10.3389/fendo.2012.00058

Genome-Wide Characterization of Menin-Dependent H3K4me3 Reveals a Specific Role for Menin

Genome-Wide Characterization of Menin-Dependent H3K4me3 Reveals a Specific Role for Menin in the Regulation of Genes Implicated in MEN1-Like Tumors
-S Agarwal, R Jothi
PLoS ONE 7(5): e37952. doi:10.1371/journal.pone.0037952

Drug-resistant hyperprolactinemia

MEN1 frequently involves pituitary disease. One study found pituitary disease occurred in 42% of MEN1 patients.⁽¹⁾ Depending on the specific type of pituitary disorder, treatment may include the surgical removal of an adenoma, the use of hormones or drugs to normalize pituitary function, or radiotherapy.

A prolactinoma, for example, is a non-cancerous pituitary tumor that produces the hormone prolactin; it's the most common form of pituitary tumor.⁽²⁾ Prolactinomas tend to cause hyperprolactinemia, abnormally high blood levels of prolactin. This can cause a variety of symptoms, including interfering with normal ovulatory function in women.

Normally, prolactin-producing cells are down-regulated, or inhibited, by dopamine signals from the hypothalamus.⁽³⁾ Therefore, hyperprolactinemia often is treated by dopamine agonists, usually Cabergoline or Bromocriptine.

Cabergoline usually is more effective than Bromocriptine at normalizing prolactin levels and restoring gonadal function.⁽⁴⁾ Yet it is not always successful in lowering prolactin to normal levels.

One particular patient, "P", was found to have hyperprolactinemia which then prompted an MRI scan and diagnosis of a pituitary adenoma. Treatment with Cabergoline was started. Within four months, the adenoma shrank and was no longer detectable via MRI, and P's prolactin level dropped to normal levels. But not for long. The prolactin level began to rise, and P's doctor responded with increasing dosage of Cabergoline. This went on for eight years, with Caborgoline dosage of up to 2.5mg/wk and prolactin levels typically about 50-100 mg/dL. When Cabergoline was discontinued, the prolactin would shoot up to about 180, and when Cabergoline was resumed, prolactin would reduce but not normalize. Periodic MRIs suggested possible empty sella syndrome and no sign of adenoma.

P's treatment subsequently was switched to Bromocriptine for a year, but her prolactin did not respond as well as it did to Cabergoline, and so Cabergoline was resumed.

What is there to do for a patient whose hyperprolactinemia does not respond sufficiently to dopamine agonist therapy, and who does not exhibit an operable adenoma?
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⁽¹⁾ Bruno Vergès, et al. Pituitary Disease in MEN Type 1 (MEN1): Data from the France-Belgium MEN1 Multicenter Study. The Journal of Clinical Endocrinology & Metabolism February 1, 2002 vol. 87 no. 2, 457-465.
⁽²⁾ http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001377/
⁽³⁾ http://en.wikipedia.org/wiki/Dopamine#Regulating_prolactin_secretion
⁽⁴⁾ Webster, et al. A Comparison of Cabergoline and Bromocriptine in the Treatment of Hyperprolactinemic Amenorrhea. N Engl J Med 1994; 331:904-909