Skeletal impact of 17β-estradiol in T cell-deficient mice: age-dependent bone effects and osteosarcoma formation

Bone‐Specific Metabolism of Dietary Polyphenols in Resorptive Bone Diseases

“…Circulating glucuronidated curcumin levels were also constant during development following oral ingestion of curcumin. However, bone substrate content was >2-fold higher in skeletally-immature, growing mice, possibly attributable to increased blood flow associated with this high turnover state and/or bone milieu changes associated with high turnover itself [51,52] . Similarly, 2.3-to 3.6-fold higher glucuronide substrate content in bone was also documented in OVX and BMET-bearing mice (vs age matched controls), two additional conditions where bone turnover is markedly enhanced, with variable effects reported on net changes in blood flow [51,53,54] .…”

Osteolytic effects of tumoral estrogen signaling in an estrogen receptor-positive breast cancer bone metastasis model

“…Because mice, unlike humans, lack aromatase expression in mammary tissue and bone cells [14,15] and also have 10-fold lower circulating 17β-estradiol (E 2 ) levels than humans [16] , the optimal growth of human ER+ breast cancer orthotopic tumors and osteolytic BMETs in preclinical murine models is dependent on exogenous E 2 supplementation [17,18,[19][20][21][22][23][24][25][26]27,28] . This presents a challenge when studying murine models of human ER+ BMETs given the responsiveness of both tumor and bone cells to E 2 [29][30][31][32][33] and the absence of syngeneic models of murine ER+ breast cancer BMET. Indeed, the E 2 doses required to promote ER+ breast cancer growth in osteolytic xenograft models also increase murine bone mass [18,20,21,26,28,34] and furthermore, can induce osteolytic murine osteosarcomas in some animals, as previously demonstrated by our laboratory [34] .…”

A Role for TGFβ Signaling in Preclinical Osteolytic Estrogen Receptor-Positive Breast Cancer Bone Metastases Progression

“…Consistent with the significant decrease in ER+ BMET-associated osteolysis documented with 1D11 treatment, osteoclast formation at the tumor-bone interface was also significantly reduced (65%) in mice treated with 1D11 (vs. controls) ( Figure 8 D). While inhibition of ER- BMET progression by 1D11 antibody treatment in mouse models lacking E 2 supplementation is accompanied by significant anabolic effects of TGFβ neutralization on the bone microenvironment [ 30 , 32 , 48 ], areal bone mineral density (aBMD) of the proximal femur, a site devoid of ER+ BMETs in all treatment groups (data not shown), was not altered by TGFβ neutralization above levels already induced by E 2 alone ( Figure 8 E), an effect that we have previously demonstrated to be attributable to enhanced anabolism [ 12 , 49 ].…”

“…Experiments were conducted using established human breast cancer cells lines rather than cells from patient-derived xenografts (PDX) models; while PDX models recapitulate aspects of patient-specific responses across a range of human tumors, ER+ PDXs are reported to have a much lower take rate and tend not to metastasize to bone [67][68][69]. Furthermore, the necessity of supplementing human xenograft ER+ BMET models with E 2 to promote tumor growth and BMETs [12,61,[70][71][72][73][74][75][76][77][78] causes notable anabolic changes in murine bone [49,61,72,79], which we previously demonstrated to have a stimulatory effect on ER+ BMETs [12], although these effects were independent of tumor-specific, pro-osteolytic effects of E 2 that also drove ER+ BMET progression in the models described here [12]. However, from an experimental standpoint, this aspect of the ER+ models had the benefit of negating the anabolic effects of TGFβ inhibition on the bone microenvironment normally seen in naïve or ER-tumorbearing mice [30,32,48].…”

“…Four-weekold female Foxn1 nu athymic nude outbred mice were purchased from Envigo (Indianapolis, IN, USA) and housed in plastic cages in laminar flow isolated hoods with access to water and autoclaved mouse chow ad libitum. Mice (n = 5-13/group) were inoculated at 5 weeks of age with 1 × 10 5 ER+ tumor cells via the left cardiac ventricle (intracardiac, IC) three days post placement of 60-day extended release 0.72 mg 17β-estradiol (E 2 ) pellets (Innovative Research of America, Sarasota, FL, USA), as previously described [12,41,49]. In one experiment, similarly E 2 -supplemented mice inoculated with BMET-derived 43-4M tumor cells (n = 5-7/group) were treated for 6 weeks with a pan-TGFβ-neutralizing murine monoclonal antibody (clone 1D11.16.8, #BE0057, BioXCell, Lebanon, NH, USA) vs. isotype-matched murine control IgG (M0PC-21 clone, #BE0083, BioXCell, Lebanon, NH, USA) or vehicle alone (in vivo Pure pH 7.0 dilution buffer, #IP0070, BioXCell, Lebanon, NH, USA).…”