In cyclic females, FSH stimulates ovarian estradiol (E2) production and follicular growth up to the terminal stage. A transient elevation in circulating FSH and E2 levels occurs shortly after birth. But what could be the action of FSH on the ovary during this period, and in particular how it stimulates ovarian steroidogenesis without supporting terminal follicular maturation is intriguing. By experimentally manipulating FSH levels, we demonstrate in mice that the mid-infantile elevation in FSH is mandatory for E2 production by the immature ovary, but that it does not stimulate follicle growth. Importantly, FSH increases aromatase expression to stimulate E2 synthesis, however it becomes unable to induce cyclin D2, a major driver of granulosa cell proliferation. Besides, although FSH prematurely induces luteinizing hormone (LH) receptor expression in granulosa cells, LH pathway is not functional in these cells to induce their terminal differentiation. In line with these results, supplying infantile mice with a superovulation regimen exacerbates E2 production, but it does not stimulate the growth of follicles and it does not induce ovulation. Overall, our findings unveil a regulation whereby high postnatal FSH concentrations ensure the supply of E2 required for programming adult reproductive function without inducing follicular maturation before puberty.

Inactivation and silencing of PTEN have been observed in multiple cancers, including follicular thyroid carcinoma. PTEN (phosphatase and tensin homologue deleted from chromosome 10) functions as a tumour suppressor by opposing the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway. Despite correlative data, how deregulated PTEN signalling leads to thyroid carcinogenesis is not known. Mice harbouring a dominant-negative mutant thyroid hormone receptor β (TRβPV/PV mice) spontaneously develop follicular thyroid carcinoma and distant metastases similar to human cancer. To elucidate the role of PTEN in thyroid carcinogenesis, we generated TRβPV/PV mice haploinsufficient for Pten (TRβPV/PVPten+/− mouse). PTEN deficiency accelerated the progression of thyroid tumour and increased the occurrence of metastasis spread to the lung in TRβPV/PVPten+/− mice, thereby significantly reducing their survival as compared with TRβPV/PVPten+/+ mice. AKT activation was further increased by two-fold in TRβPV/PVPten+/− mice thyroids, leading to increased activity of the downstream mammalian target of rapamycin (mTOR)–p70S6K signalling and decreased activity of the forkhead family member FOXO3a. Consistently, cyclin D1 expression was increased. Apoptosis was decreased as indicated by increased expression of nuclear factor-κB (NF-κB) and decreased caspase-3 activity in the thyroids of TRβPV/PVPten+/− mice. Our results indicate that PTEN deficiency resulted in increased cell proliferation and survival in the thyroids of TRβPV/PVPten+/− mice. Altogether, our study provides direct evidence to indicate that in vivo, PTEN is a critical regulator in the follicular thyroid cancer progression and invasiveness.

We previously created a knock-in mutant mouse harboring a dominantly negative mutant thyroid hormone receptor ␤ (TR␤ PV/PV mouse) that spontaneously develops a follicular thyroid carcinoma similar to human thyroid cancer. We found that ␤-catenin, which plays a critical role in oncogenesis, was highly elevated in thyroid tumors of TR␤ PV/PV mice. We sought to understand the molecular basis underlying aberrant accumulation of ␤-catenin by mutations of TR␤ in vivo. Cell-based studies showed that thyroid hormone (T3) induced the degradation of ␤-catenin in cells expressing TR␤ via proteasomal pathways. In contrast, no T3-induced degradation occurred in cells expressing the mutant receptor (TR␤PV). In vitro binding studies and cell-based analyses revealed that ␤-catenin physically associated with unliganded TR␤ or TR␤PV. However, in the presence of T3, ␤-catenin was dissociated from TR␤-␤-catenin complexes but not from TR␤PV-␤-catenin complexes. ␤-Catenin signaling was repressed by T3 in TR␤-expressing cells through decreasing ␤-catenin-mediated transcription activity and target gene expression, whereas sustained ␤-catenin signaling was observed in TR␤PV-expressing cells. The stabilization of ␤-catenin, via association with a mutated TR␤, represents a novel activating mechanism of the oncogenic protein ␤-catenin that could contribute to thyroid carcinogenesis in TR␤ PV/PV mice.