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New Selective Progesterone Receptor Modulators and Their Impact on the RANK/RANKL Complex Activity

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New Selective Progesterone Receptor Modulators and Their Impact on the RANK/RANKL Complex Activity molecules Article New Selective Progesterone Receptor Modulators and Their Impact on the RANK/RANKL Complex Activity Katarzyna Błaszczak-Swi´ ˛atkiewicz Department of Applied Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland; [email protected]; Tel.: +48-426779240 Academic Editors: Simona Collina and Mariarosaria Miloso Received: 8 February 2020; Accepted: 11 March 2020; Published: 13 March 2020 Abstract: Breast cancer depends on women’s age. Its chemotherapy and hormone therapy lead to the loss of bone density and disruption of the skeleton. The proteins RANK and RANKL play a pivotal role in the formation of osteoclasts. It is also well established that the same proteins (RANK and RANKL) are the main molecules that play an important role in mammary stem cell biology. Mammary stem cells guarantee differentiation of the epithelial mammary cells, the growth of which is regulated by the progesterone-induced RANKL signaling pathway. The crosstalk between progesterone receptor, stimulated by progesterone and its analogues results in RANKL to RANK binding and activation of cell proliferation and subsequently unlimited expansion of the breast cancer cells. Therefore downstream regulation of this signaling pathway is desirable. To meet this need, a new class of selective estrogen receptor modulators (SPRMs) with anti- and mesoprogestin function were tested as potential anti-RANK agents. To establish the new feature of SPRMs, the impact of tested SPRMs on RANK-RANKL proteins interaction was tested. Furthermore, the cells proliferation upon RANKL stimulation, as well as NFkB and cyclin D1 expression, induced by tested SPRMs were analyzed. Conducted experiments proved NFkB expression inhibition as well as cyclin D1 expression limitation under asoprisnil and ulipristal treatment. The established paracrine anti-proliferative activity of antiprogestins together with competitive interaction with RANK make this class of compounds attractive for further study in order to deliver more evidence of their anti-RANK activity and potential application in the breast cancer therapy together with its accompanied osteoporosis. Keywords: RANK-RANKL complex; antiprogestins; mesoprogestins; osteoporosis; breast cancer 1. Introduction Breast cancer is a disorder which depends on the women’s age and hormonal system activity [1]. Estradiol determines the growth of mammary stem cells. It is well established that receptor activator of nuclear factor κB (RANK, the receptor for RANKL) and receptor activator of nuclear factor kappa-B ligand (RANKL) are the main molecules that play an important role in mammary stem cell biology. Differentiation of epithelial mammary cells is regulated by the progesterone-induced RANKL signaling pathway. Crosstalk between progesterone receptor, stimulated by progesterone, is expressed by the interaction between the progesterone receptor and RANKL, results in RANKL to RANK binding and activates cell proliferation and subsequently unlimited expansion of the breast cancer cells. Moreover, the same RANK-RANKL complex plays a pivotal role in osteoclastogenesis [2]. Osteoporosis often accompanies breast cancer treatment with selective estrogen receptor modulators (SERMs) and is a common disease, especially among menopausal women [3]. Estradiol deficiency during menopause or surgical removal of the ovaries is responsible for the loss of bone density in the female body. Although a similar bone density reduction effect is observed in correlation to low testosterone levels in the male body, osteoporosis is more common for women than men. The statistical analysis proves about 15% of Molecules 2020, 25, 1321; doi:10.3390/molecules25061321 www.mdpi.com/journal/molecules MoleculesMoleculesMoleculesMolecules 20202020 2020 2020,, 2424, ,24, , x x24, x, x 22 of2of 2of 9 9 of 9 9 Moleculeswomenwomenwomenwomen2020 [3].[3]. [3]., 25 [3]. EstradiolEstradiol ,Estradiol 1321 Estradiol deficiencydeficiency deficiency deficiency duringduring during during menopausemenopause menopause menopause oror or surgical surgicalor surgical surgical removalremoval removal removal ofof of the theof the the ovariesovaries ovaries ovaries isis is responsibleresponsible is responsible responsible2 of 9 forforfor forthethe the the lossloss loss loss ofof of boneboneof bone bone densitydensity density density inin in thethein the the femalefemale female female body.body. body. body. AlAl Although thoughAlthoughthough aa similarasimilar asimilar similar bonebone bone bone densitydensity density density reductionreduction reduction reduction effecteffect effect effect isis is is observedobservedobservedobserved inin Moleculesin correlationcorrelation in correlation correlation 2020, 24 toto, xto lowlow to low low testosteronetestosterone testosterone testosterone levelslevels levels levels inin in thethe in the the malemale male male body,body, body, body, osteoporosisosteoporosis osteoporosis osteoporosis isis is moremore is more more commoncommon common common 2forfor offor for9 people in their 50 s and 70% of those over 80 have osteoporosis [4]. The expression of RANK-RANKL womenwomenwomenwomen thanthan than than men.men. men. men. 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Although a similar bone density reduction effect is andbiologicalbiologicalbiological indirectlybiological responseresponse response byresponse expression pathways:pathways: pathways: pathways: of thedirectlydirectly directly progesteronedirectly byby by byinteractioninteraction interaction interaction receptor. withwith with Thewith RANK/RANKLRANK/RANKL firstRANK/RANKLRANK/RANKL way is based andand and and onindirectlyindirectly indirectly theindirectly activity byby by by of observed in correlation to low testosterone levels in the male body, osteoporosis is more common for osteoprotegerinexpression of (OPG)the progesterone as a decoy receptor. receptor The for first RANKL. way is The based second on the one activity is an interactionof osteoprotegerin between expressionexpressionexpression womenofof thetheof the progesteroneprogesteronethan progesterone men. The receptor.statisticalreceptor. receptor. analysis TheThe The firstfirst provesfirst wayway way about isis based basedis 15% based onofon people onthethe the activityactivity in activity their of of50 osteoprotegerinosteoprotegerinsof and osteoprotegerin 70% of those the(OPG)(OPG)(OPG) progesterone(OPG) asas as aaas overadecoydecoy adecoy decoy 80 receptor receptor receptor havereceptor receptor osteoporosis (PR) forfor for forRANKL.RANKL. ligand RANKL. RANKL. [4]. and TheTheThe The progesterone.The secondsecondexpressi second second oneoneon one one of isis is TheanRANK-RANKLan is an interactionaninteraction osteoprotegerininteraction interaction betweenbetweenmolecules between between expression thethe goesthe the progesteroneprogesterone progesterone throughprogesterone is induced two byreceptorreceptor femalereceptorreceptor (PR)(PR) sex (PR)biological (PR) hormonesligandligand ligand ligand responseandand and andand progesterone.progesterone. progesterone. progesterone. inhibitspathways: the ThedirectlyThe The development The osteoprotegerinosteoprotegerin osteoprotegerin osteoprotegerinby interaction and expression expression activation withexpression expression RANK/RANKL is ofis is inducedinduced osteoclasts,is induced induced and byby by byfemaleindirectlyfemale whichfemale female sexsex in sexby sex the longhormoneshormoneshormoneshormones run results andandexpression and and inhibitsinhibits in inhibits inhibits the of inhibitionthe thethe the the development developmentprogesterone development development of bone receptor. andand loss.and and activationactivation activation OPGactivationThe first is ofof the wayof osteoclasts, osteoclasts,of osteoclasts, main osteoclasts,is based regulator onwhichwhich which thewhich activityin ofin in the thein the the long long crosstalkof long osteoprotegerinlong runrun run run resultsresults betweenresults results estrogenininin thethein the the inhibitioninhibition andinhibition inhibition(OPG) RANKL ofasof of aboneboneof decoybone expression bone loss.loss. receptorloss. loss. OPGOPG OPG referringOPG for isis RANKL.is thetheis the the mainmain tomain mainThe the regulatorregulator secondregulator bone regulator destructionone ofof of is thetheof anthe the crosstinteractioncrosst crosst crosst repressionalkalkalk alk between betweenbetween between between [2]. theestrogenestrogen Toestrogen progesteroneestrogen prevent andand and and the overexpressionRANKLRANKLRANKLRANKL expressionexpression expressionreceptor expression of osteoclasts (PR)referringreferring referring referring ligand to into toand the osteoporosis,theto
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