Selective Estrogen Receptor Down-Regulator and Selective Estrogen Receptor Modulators Differentially Regulate Lactotroph Proliferation

occupation, differentially modulates the biological outcome of anti-estrogens. expression and release, as well as ERE-mediated transcriptional activity. expression

Tamoxifen may prevent both ER+ and ER- breast cancers and select for ER- carcinogenesis: an alternative hypothesis

INTRODUCTION: Breast Cancer Prevention Trial (BCPT) and Multiple Outcomes of Raloxifene (MORE) data have been interpreted to indicate that tamoxifen reduces the risk of ER+ but not ER- breast carcinogenesis. We explored whether these data also support an alternative hypothesis, that tamoxifen influences the natural history of both ER+ and ER- cancers, that it may be equally effective in abrogating or delaying ER- and ER+ carcinogenesis, and place selection pressure, in some cases, for the outgrowth of ER- cancers. METHODS: BCPT and MORE data were used to investigate whether: first, tamoxifen could reduce equally the emergence of ER- and ER+ tumors; and second, tamoxifen could select a fraction of emerging ER+ cancers and promote their transformation to ER- cancers. Assuming that some proportion, Z, of ER+ tumors becomes ER- after tamoxifen exposure and that the risk reduction for both ER- and ER+ tumors is equal, we solved for both the transformation rate and the risk reduction rate. RESULTS: If tamoxifen equally reduces the incidence of ER+ and ER- tumors by 60%, the BCPT results are achieved with a transformation of approximately Z = 20% of ER+ to ER- tumors. Validation with MORE data using an equal risk reduction of 60% associated with tamoxifen produces an almost identical transformation rate Z of 23%. CONCLUSION: Data support an alternative hypothesis that tamoxifen may promote ER- carcinogenesis from a precursor lesion that would otherwise have developed as ER+ without tamoxifen selection

Generation of Immortal Cell Lines from the Adult Pituitary: Role of cAMP on Differentiation of SOX2-Expressing Progenitor Cells to Mature Gonadotropes

The pituitary is a complex endocrine tissue composed of a number of unique cell types distinguished by the expression and secretion of specific hormones, which in turn control critical components of overall physiology. The basic function of these cells is understood; however, the molecular events involved in their hormonal regulation are not yet fully defined. While previously established cell lines have provided much insight into these regulatory mechanisms, the availability of representative cell lines from each cell lineage is limited, and currently none are derived from adult pituitary. We have therefore used retroviral transfer of SV40 T-antigen to mass immortalize primary pituitary cell culture from an adult mouse. We have generated 19 mixed cell cultures that contain cells from pituitary cell lineages, as determined by RT-PCR analysis and immunocytochemistry for specific hormones. Some lines expressed markers associated with multipotent adult progenitor cells or transit-amplifying cells, including SOX2, nestin, S100, and SOX9. The progenitor lines were exposed to an adenylate cyclase activator, forskolin, over 7 days and were induced to differentiate to a more mature gonadotrope cell, expressing significant levels of α-subunit, LHβ, and FSHβ mRNAs. Additionally, clonal populations of differentiated gonadotropes were exposed to 30 nM gonadotropin-releasing hormone and responded appropriately with a significant increase in α-subunit and LHβ transcription. Further, exposure of the lines to a pulse paradigm of GnRH, in combination with 17β-estradiol and dexamethasone, significantly increased GnRH receptor mRNA levels. This array of adult-derived pituitary cell models will be valuable for both studies of progenitor cell characteristics and modulation, and the molecular analysis of individual pituitary cell lineages

Estrogen Receptor Beta rs1271572 Polymorphism and Invasive Ovarian Carcinoma Risk: Pooled Analysis within the Ovarian Cancer Association Consortium

The association of ovarian carcinoma risk with the polymorphism rs1271572 in the estrogen receptor beta (ESR2) gene was examined in 4946 women with primary invasive ovarian carcinoma and 6582 controls in a pooled analysis of ten case-control studies within the Ovarian Cancer Association Consortium (OCAC). All participants were non-Hispanic white women. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression adjusted for site and age. Women with the TT genotype were at increased risk of ovarian carcinoma compared to carriers of the G allele (OR = 1.10; 95%; CI: 1.01–1.21; p = 0.04); the OR was 1.09 (CI: 0.99–1.20; p = 0.07) after excluding data from the center (Hawaii) that nominated this SNP for OCAC genotyping A stronger association of rs1271572 TT versus GT/GG with risk was observed among women aged ≤50 years versus older women (OR = 1.35; CI: 1.12–1.62; p = 0.002; p for interaction = 0.02) that remained statistically significant after excluding Hawaii data (OR = 1.34; CI: 1.11–1.61; p = 0.009). No heterogeneity of the association was observed by study, menopausal status, gravidity, parity, use of contraceptive or menopausal hormones, tumor histological type, or stage at diagnosis. This pooled analysis suggests that rs1271572 might influence the risk of ovarian cancer, in particular among younger women

Lineage-Specific Restraint of Pituitary Gonadotroph Cell Adenoma Growth

Although pituitary adenomas are usually benign, unique trophic mechanisms restraining cell proliferation are unclear. As GH-secreting adenomas are associated with p53/p21-dependent senescence, we tested mechanisms constraining non-functioning pituitary adenoma growth. Thirty six gonadotroph-derived non-functioning pituitary adenomas all exhibited DNA damage, but undetectable p21 expression. However, these adenomas all expressed p16, and >90% abundantly expressed cytoplasmic clusterin associated with induction of the Cdk inhibitor p15 in 70% of gonadotroph and in 26% of somatotroph lineage adenomas (p = 0.006). Murine LβT2 and αT3 gonadotroph pituitary cells, and αGSU.PTTG transgenic mice with targeted gonadotroph cell adenomas also abundantly expressed clusterin and exhibited features of oncogene-induced senescence as evidenced by C/EBPβ and C/EBPδ induction. In turn, C/EBPs activated the clusterin promoter ∼5 fold, and elevated clusterin subsequently elicited p15 and p16 expression, acting to arrest murine gonadotroph cell proliferation. In contrast, specific clusterin suppression by RNAis enhanced gonadotroph proliferation. FOXL2, a tissue-specific gonadotroph lineage factor, also induced the clusterin promoter ∼3 fold in αT3 pituitary cells. As nine of 12 pituitary carcinomas were devoid of clusterin expression, this protein may limit proliferation of benign adenomatous pituitary cells. These results point to lineage-specific pathways restricting uncontrolled murine and human pituitary gonadotroph adenoma cell growth

Regulation of hormone signaling by nuclear receptor interacting proteins.

The original publication is available at springerlink.comInternational audienceNuclear receptors are ligand-activated transcription factors which regulate the expression of genes critical for the growth of hormone-dependent cancers. Their expression and activity are controlled by various cofactors which are important players in hormone-dependent carcinogenesis. RIP140 is a negative transcriptional regulator which is recruited by agonist-liganded receptors. Its strong repressive activity involves four silencing domains which interact with histone deacetylases (HDACs), carboxyl-terminal binding proteins (CtBPs) and additional partners. RIP140 positively regulates transactivation when nuclear receptors are recruited to target promoters through interaction with the Sp1 transcription factor. In human breast cancer cells, RIP140 expression is upregulated at the transcriptional level by various ligands of nuclear receptors revealing the existence of regulatory loops. The Mdm2 oncogenic ubiquitin-ligase is another protein which directly interacts with nuclear receptors. It is involved in a ternary complex with ERΑ and p53 and regulates ERΑ turn-over. In MCF-7 human breast cancer cells, various p53-inducing agents (such as UV irradiation) abolished E2-dependent turn-over of ERΑ without affecting its transactivation potential. Altogether, our results show that RIP140 and Mdm2 are two important regulators of ERΑ expression and activity and could therefore play major roles in hormone-dependent breast carcinogenesis