Sex-Related Differences in Lactotroph Tumor Aggressiveness Are Associated With a Specific Gene-Expression Signature and Genome Instability

Abstract

Sex-related differences have been reported in various cancers, in particular men with lactotroph tumors have a worse prognosis than women. While the underlying mechanism of this sexual dimorphism remains unclear, it has been suggested that a lower estrogen receptor alpha expression may drive the sex differences observed in aggressive and malignant lactotroph tumors that are resistant to dopamine agonists. Based on this observation, we aimed to explore the molecular importance of the estrogen pathway through a detailed analysis of the transcriptomic profile of lactotroph tumors from 20 men and 10 women. We undertook gene expression analysis of the selected lactotroph tumors following their pathological grading using the five-tiered classification. Chromosomic alterations were further determined in 13 tumors. Functional analysis showed that there were differences between tumors from men and women in gene signatures associated with cell morphology, cell growth, cell proliferation, development, and cell movement. Hundred-forty genes showed an increased or decreased expression with a minimum 2-fold change. A large subset of those genes belonged to the estrogen receptor signaling pathway, therefore confirming the potent role of this pathway in lactotroph tumor sex-associated aggressiveness. Genes belonging to the X chromosome, such as CTAG2, FGF13, and VEGF-D, were identified as appealing candidates with a sex-linked dysregulation in lactotroph tumors. Through our comparative genomic hybridization analyses (CGH), chromosomic gain, in particular chromosome 19p, was found only in tumors from men, while deletion of chromosome 11 was sex-independent, as it was found in most (5/6) of the aggressive and malignant tumors. Comparison of transcriptomic and CGH analysis revealed four genes (CRB3, FAM138F, MATK, and STAP2) located on gained regions of chromosome 19 and upregulated in lactotroph tumors from men. MATK and STAP2 are both implicated in cell growth and are reported to be associated with the estrogen signaling pathway. Our work confirms the proposed involvement of the estrogen signaling pathway in favoring the increased aggressiveness of lactotroph tumors in men. More importantly, we highlight a number of ER-related candidate genes and further identify a series of target molecules with sex-specific expression that could contribute to the aggressive behavior of lactotroph tumors in men.

Pituitary Hyperplasia, Hormonal Changes and Prolactinoma Development in Males Exposed to Estrogens—An Insight From Translational Studies

“…Estrogen may affect already-differentiated PRL cells, stem/progenitor cells, lineage-related cells and cells comprising the microenvironment. Transcriptional regulation of the following genes is mainly associated with tumorigenic action of estrogen in the pituitary: pituitary tumor transforming gene (PTTG); Myc; aldehyde dehydrogenase 1A1 (ALDH1A1); D2R, dopamine D2 receptor; mitogen-activated protein kinases (MAPK); vascular endothelial growth factor (VEGF); fibroblast growth factor 2 (FGF2); transforming growth factor β (TGFβ) and other growth factors and cytokines, such as ILs, interleukines [15,16,[40][41][42][43][44][45][46][47][48][49][50][51][52][53].…”

“…Aside from its normal physiology, ERα-mediated signaling is important for development of the pituitary prolactinomas and may also be involved in increased aggressiveness of lactotropic tumors in men [15] (Figure 3). Estrogen was the first-discovered inducer of pituitary tumor transforming gene (Pttg) through its nuclear ERα, a well-known proto-oncogene whose aberrant accumulation is known to cause genetic instability that could underlie cancer development [43] (Figure 1).…”

“…Wierinckx and associates [15] used the most advanced methods (including transcriptomic, microarray and comparative genomic hybridization analyses) to examine potential sex-linked dysregulation in aggressive lactotropic tumors that are less sensitive to dopamine agonists in men. Aside from low expression of ERα, some genes from the X chromosome (Ctag2, Fgf13 and VEGFD) and chromosome 19p (STAP2) were found to be upregulated in lactotropic tumors, only in men [15].…”

“…Wierinckx and associates [15] used the most advanced methods (including transcriptomic, microarray and comparative genomic hybridization analyses) to examine potential sex-linked dysregulation in aggressive lactotropic tumors that are less sensitive to dopamine agonists in men. Aside from low expression of ERα, some genes from the X chromosome (Ctag2, Fgf13 and VEGFD) and chromosome 19p (STAP2) were found to be upregulated in lactotropic tumors, only in men [15]. Cancer testis antigen (Ctag2), whose expression correlated with various markers of aggressiveness in male prolactinomas, is implicated in the aggressive behavior of breast cancer [75] and repression of estrogen signaling [76].…”

“…To date, these sex-related differences have not been fully understood. Most recent basic research, using single-cell genomic approaches, has shed some light on sex-specific expression of genes in lactotropic cells that may, at least in part, underlie the observed differences [14][15][16].…”