Physiology et physiopathology of membrane estrogen receptor alpha (ERα) in mammary gland

It is well established that the 17-estradiol is involved in the development and homeostasis of reproductive and extra-reproductive tissues, particularly the mammary gland. Estradiol classically binds to Estrogen Receptor (ERα), which is a member of the nuclear receptor superfamily. ER mediates nuclear (transcription) and plasma membrane (signaling) ERα function. Interestingly, the membrane initiated steroid signaling (MISS) required a post translational modification of the receptor: palmitoylation of the human Cys-447 or the murine Cys-451 counterpart. The main objectives of my PhD thesis were to decipher the physiological role of membrane ERα in mammary gland development and to understand how the membrane ER signaling impact breast cancer. To do so, we used the transgenic mouse model C451A-ER in which the single point mutation (C451A) was introduced to abolish palmitoylation of ER (membrane addressing signal). We demonstrate that the point mutation of the palmitoylation site of ER alters the paracrine signaling of luminal epithelial cells and by consequence the repopulation properties of the mammary stem cells. We also studied the involvement of the membrane effects of the Estrogen Receptor ERα in the 17β-estradiol response dose of the mammary gland. Finally, by breeding the C451A-ER mice with the widely used transgenic mice model of tumorigenesis (PyMT), we provide the first evidence that the membrane ERα influences tumorigenesis. These findings pave the way on an unexpected role of non-genomic function of ERα in the mammary gland physiology and physiopathology.It is well established that the 17-estradiol is involved in the development and homeostasis of reproductive and extra-reproductive tissues, particularly the mammary gland. Estradiol classically binds to Estrogen Receptor (ERα), which is a member of the nuclear receptor superfamily. ER mediates nuclear (transcription) and plasma membrane (signaling) ERα function. Interestingly, the membrane initiated steroid signaling (MISS) required a post translational modification of the receptor: palmitoylation of the human Cys-447 or the murine Cys-451 counterpart. The main objectives of my PhD thesis were to decipher the physiological role of membrane ERα in mammary gland development and to understand how the membrane ER signaling impact breast cancer. To do so, we used the transgenic mouse model C451A-ER in which the single point mutation (C451A) was introduced to abolish palmitoylation of ER (membrane addressing signal). We demonstrate that the point mutation of the palmitoylation site of ER alters the paracrine signaling of luminal epithelial cells and by consequence the repopulation properties of the mammary stem cells. We also studied the involvement of the membrane effects of the Estrogen Receptor ERα in the 17β-estradiol response dose of the mammary gland. Finally, by breeding the C451A-ER mice with the widely used transgenic mice model of tumorigenesis (PyMT), we provide the first evidence that the membrane ERα influences tumorigenesis. These findings pave the way on an unexpected role of non-genomic function of ERα in the mammary gland physiology and physiopathology

The follicle-stimulating hormone signaling network in Sertoli cells

Chapitre 6absen

The follicle-stimulating hormone signaling network in gonadal cells.

International audienceFSH (follicle-stimulating hormone) is a master endocrine regulator of somatic cells of the gonads that support gametogenesis. In the male, FSH dictates the Sertoli cell proliferation rate prior to puberty, then maintains their main biological roles as nurturing cells and physical support to spermatogenesis throughout life. In the female, FSH is instrumental in processing the terminal differentiation phase of folliculogenesis that progressively drives the ovarian follicle to ovulation. The biological function of FSH is transduced by a membrane receptor, the FSH receptor (FSHR). Deciphering the molecular bases of the developmental switch in FSH biological activities is required to gain insights into FSH-induced signaling pathways. This quest has led to the identification of a complex interconnected signaling network affected by testicular paracrine factors, implying not only protein post-translational modifications but also regulation by microRNA and chromatin remodeling. In the female, the emphasis is now placed on deciphering the complex functional relationships between the LHCGR (luteinizing hormone/choriogonadotropin hormone receptor) and the FSHR that trigger intertwined signaling networks in the same granulosa cell type. Breakthroughs in the organization and dynamic functioning of the FSH-induced signaling network are expected to identifying novel regulatory processes and therapeutic strategies for infertilities and contraception

Membrane expression of the estrogen receptor ER alpha is required for intercellular communications in the mammary epithelium

17 beta-Estradiol induces the postnatal development of mammary gland and influences breast carcinogenesis by binding to the estrogen receptor ER alpha. ER alpha acts as a transcription factor but also elicits rapid signaling through a fraction of ER alpha expressed at the membrane. Here, we have used the C451A-ER alpha mouse model mutated for the palmitoylation site to understand how ER alpha membrane signaling affects mammary gland development. Although the overall structure of physiological mammary gland development is slightly affected, both epithelial fragments and basal cells isolated from C451A-ER alpha mammary glands failed to grow when engrafted into cleared wild-type fat pads, even in pregnant hosts. Similarly, basal cells purified from hormone-stimulated ovariectomized C451A-ER alpha mice did not produce normal outgrowths. Ex vivo, C451A-ER alpha basal cells displayed reduced matrix degradation capacities, suggesting altered migration properties. More importantly, C451A-ER alpha basal cells recovered in vivo repopulating ability when co-transplanted with wild-type luminal cells and specifically with ER alpha-positive luminal cells. Transcriptional profiling identified crucial paracrine luminal-to-basal signals. Altogether, our findings uncover an important role for membrane ER alpha expression in promoting intercellular communications that are essential for mammary gland development