Abstract
Locally produced growth hormone (GH) and IGF-I are key factors in the regulation of mammary gland (MG) development and may be important in breast cancer development/progression. Somatostatin (SST) and cortistatin (CORT) regulate GH/IGF-I axis at various levels, but their role in regulating GH/IGF-I in MGs remains unknown. Since obesity alters the expression of these systems in different tissues and is associated to MG (patho) physiology, we sought to investigate the role of SST/CORT in regulating GH/IGF-I system in the MGs of lean and obese mice. Therefore, we analyzed GH/IGF-I as well as SST/CORT and ghrelin systems expression in the mammary fat pads (MFPs) of SST- or CORT-knockout (KO) mice and their respective littermate-controls fed a low-fat (LF) or a high-fat (HF) diet for 16wks. Our results demonstrate that the majority of the components of GH/IGF-I, SST/CORT and ghrelin systems are locally expressed in mouse MFP. Expression of elements of the GH/IGF-I axis was significantly increased in MFPs of HF-fed control mice while lack of endogenous SST partially suppressed, and lack of CORT completely blunted, the up-regulation observed in obese WT-controls. Since SST/CORT are known to exert an inhibitory role on the GH/IGFI axis, the increase in SST/CORT-receptor sst2 expression in MFPs of HF-fed CORT- and SST-KOs together with an elevation on circulating SST in CORT-KOs could explain the differences observed. These results offer new information on the factors (GH/IGF-I axis) involved in the endocrine/metabolic dysregulation of MFPs in obesity, and suggest that CORT is not a mere SST sibling in regulating MG physiology.
Highlights
The growth hormone (GH) / insulin-like growth factor I (IGF-I) axis plays a crucial role in mammary gland development and breast cancer progression [1,2,3]
IGF-I, IGF-IR, GH and its receptor (GH-R) and PRL-R [53] are expressed at high levels in mouse mammary fat pads (MFPs), while GH expression is barely detectable, at least in mature female mice
These data are consistent with previous studies [4] and reinforce the idea that circulating, rather than locally produced GH acts on MFPs through GH-R to stimulate IGF-I production, which, in turn, can be acting in an autocrine or paracrine fashion to regulate mammary gland development [3,10,11,12,13,14,54,55]
Summary
The growth hormone (GH) / insulin-like growth factor I (IGF-I) axis plays a crucial role in mammary gland development and breast cancer progression [1,2,3]. Locally produced GH does not substitute for circulating GH in terms of promotion of mammary gland development [8]. In this context, the main action of circulating/local GH on the mammary fat pads (MFPs) seems to be stimulation of IGF-I production, as it has been shown that IGF-I mediates all of the actions of GH in mammary gland morphogenesis [2,9,10]. IGF-I, which is locally expressed in MFPs [11] and in mammary gland epithelium [12,13], plays a direct role in ductal morphogenesis and mammary gland development. Regulation of mammary gland physiology by this system is likely more complex, as it interacts with other related peptides, such as prolactin (PRL), and its receptor (PRL-R), which is a well-known key regulatory tandem of mammary gland development and physiology [15]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
