Phosphatidylinositol-3-kinase (PI3K) is a central mediator of all receptor tyrosine kinase-initiated signaling cascades, catalyzing the conversion of phosphatidylinositol (4,5)-biphosphate (PIP-2) into phosphatidylinositol (3,4,5)-triphosphate (PIP-3). One major effector of PI3K is the AKT kinase, which is activated upon PIP-3-mediated membrane recruitment and, in turn, phosphorylates an ever-growing list of target proteins, regulating key processes such as proliferation, survival, cell size, and mRNA translation (Figure 1). This process is counteracted by the PTEN tumor suppressor, which opposes PI3K activity by dephosphorylating PIP-3 to PIP-2. Heterozygous mutation of PTEN causes Cowden disease, a dominant genetic syndrome whose characteristics include an increased risk for developing breast, endometrial and thyroid cancer. Somatic deletions or mutations of PTEN have been identified in a large fraction (12-60%) of tumors, placing PTEN among the most commonly mutated genes in human cancer.
Our laboratory utilizes genetically engineered mice as model systems to dissect the genetic and biochemical events consequent to loss of PTEN that lead to the transition from normal to hyperplastic and neoplastic epithelium, in particular in the endometrium and the thyroid.
We have recently shown that loss of Pten in the mouse endometrium activates Akt, and results in increased phosphorylation of estrogen receptor alpha (ERa) on serine 167. ERa phosphorylation results, in turn, in the activation of this nuclear receptor both in vivo and in vitro, even in the absence of ligand, and in its increased ability to activate the transcription of several of its target genes. In fact, loss of Pten and activation of Akt result in vivo in a considerable increase in the mRNA levels of several estrogen target genes, suggesting that Akt-mediated phosphorylation of ERa can significantly enhance the receptor activity, and thus contribute to the initiation of the neoplastic process.
To gain insights into the role PTEN plays in thyroid function and disease, we have generated a mouse strain in which Cre-mediated recombination is utilized to specifically delete Pten in the thyrocytes. We found that Pten mutant mice develop diffuse goiter characterized by a significant increase in the thyrocyte proliferative index, which is more prominent in the female mice, and in increased cell density in the female thyroid glands. In addition, we have demonstrated that a large part of TSH-induced proliferation signals are funneled through the PI3K/AKT cascade. Although complete loss of Pten is not sufficient to cause invasive tumors, over two thirds of the mutant females develop follicular adenomas by 10 months of age, demonstrating that loss of Pten renders the thyroid highly susceptible to neoplastic transformation through mechanisms that include increased thyrocyte proliferation. Our findings show that constitutive activation of the PI3K/AKT cascade is sufficient to stimulate continuous autonomous growth, and provide novel clues to the pathogenesis of Cowden Disease and sporadic nontoxic goiter.