Transgenic mice overexpressing the LH receptor in the female reproductive system spontaneously develop endometrial tumour masses

Abstract

The receptor for the luteinizing hormone (LH-R) is aberrantly over expressed in cancers of the reproductive system. To uncover whether LH-R over expression has a causative role in cancer, we generated a transgenic (TG) mouse which overexpresses the human LH-R (hLH-R) in the female reproductive tract, under the control of the oviduct-specific glycoprotein (OGP) mouse promoter (mogp-1). The transgene was highly expressed in the uterus, ovary and liver, but only in the uterus morphological and molecular alterations (increased proliferation and trans-differentiation in the endometrial layer) were detected. A transcriptomic analysis on the uteri of young TG mice showed an up regulation of genes involved in cell cycle control and a down regulation of genes related to the immune system and the metabolism of xenobiotics. Aged TG females developed tumor masses in the uteri, which resembled an Endometrial Cancer (EC). Microarray and immunohistochemistry data indicated the deregulation of signaling pathways which are known to be altered in human ECs. The analysis of a cohort of 126 human ECs showed that LH-R overexpression is associated with early-stage tumors. Overall, our data led support to conclude that LH-R overexpression may directly contribute to trigger the neoplastic transformation of the endometrium.

The Roles of Luteinizing Hormone, Follicle-Stimulating Hormone and Testosterone in Spermatogenesis and Folliculogenesis Revisited

“…Recently, it was shown that knock-in mice expressing a constitutively activating LHR are infertile, presenting with anovulation, hormonal alterations and polycystic ovaries. Likewise, transgenic mice overexpressing the LH receptor in the female reproductive system spontaneously develop endometrial tumor [ 135 , 136 ].…”

Novel roles of luteinizing hormone (LH) in tissue regeneration-associated functions in endometrial stem cells

“…Until now, the possible direct effects of LH administration on endometrial receptivity and subsequent pregnancy rates remain controversial because of conflicting results from various human studies. To date, some studies have identified some beneficial effects of LH [ 57 – 60 ], whereas other studies have reported its adverse effects [ 18 , 61 , 62 ] on endometrial receptivity. In addition, according to several previous studies, it is known that the pregnancy rates of LH receptor knockout mice were reduced compared to normal mice [ 63 ].…”

“…Importantly, the functional LH receptor (LHR), which was previously considered to be gonad tissue- or cell-specific, is highly expressed in the extragonadal endometrial tissue throughout the menstrual cycle [ 17 , 18 ]. It was recently observed that LH affects the uterine endometrium by promoting the differentiation of endometrial fibroblasts into fully differentiated decidual cells, which are essential for embryo implantation [ 19 ].…”

Locus Coeruleus Neurons’ Firing Pattern Is Regulated by ERG Voltage-Gated K+ Channels

“…Nuclei were stained with Hoechst (1:1000 in PBS, 45 minutes; Merck Sigma). Images were captured using a Nikon TE2000 confocal microscope, as described in Lottini, et al, 2021 [ 59 ].…”