Partial Hormone Resistance in Mice with Disruption of the Steroid Receptor Coactivator-1 (SRC-1) Gene

Xu, Jianming; Qiu, Yuhong; DeMayo, Francesco J.; Tsai, Sophia Y.; Tsai, Ming‐Jer; O’Malley, Bert W.

doi:10.1126/science.279.5358.1922

Cited by 637 publications

(508 citation statements)

References 21 publications

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“…Finally, an additional possibility for the differential effects of loss of SRC-1 on trabecular bone in female vs. male mice could be related to compensation for loss of SRC-1 by SRC-2 in male, but not in female mice. While SRC-2 was found to be overexpressed in the brain and testis of SRC-1 KO mice [12], testing this is considerably more difficult for trabecular bone, given the inability to isolate RNA from purely this bone compartment and this will require further studies using more complicated techniques such as in situ hybridization.…”

Section: Discussionmentioning

confidence: 99%

“…The generation of the SRC-1 KO mice has previously been described [11], and the mice used in the present studies had been extensively back-crossed (for 7 or more generations) into the C57BL/6 background. The animals were housed in a temperature-controlled room (22 ± 2° C) with a daily light/dark schedule of 12 h. During the experiments the animals had free access to water and were pair fed a standard laboratory chow (Laboratory Rodent Diet 5001, PMI Feeds, Richmond, VA) containing 0.95% calcium.…”

Section: Generation and Care Of Micementioning

confidence: 99%

“…The animals were housed in a temperature-controlled room (22 ± 2° C) with a daily light/dark schedule of 12 h. During the experiments the animals had free access to water and were pair fed a standard laboratory chow (Laboratory Rodent Diet 5001, PMI Feeds, Richmond, VA) containing 0.95% calcium. Pups were genotyped at 4 weeks of age by polymerase chain reaction (PCR) as described previously [11]. The Institutional Animal Care and Use Committee approved all animal procedures.…”

Section: Generation and Care Of Micementioning

confidence: 99%

“…The physiological importance of SRC-1 for E action has been demonstrated by the generation of SRC-1 KO mice, using conventional gene targeting [11]. The targeting event inserted an inframe stop codon at the Met 381 in exon 4, causing a downstream deletion of the genomic sequence and disruption of the SRC-1 functional domains.…”

Section: Introductionmentioning

confidence: 99%

“…The homozygous mutants are viable and fertile in both sexes but, at least in females, exhibit significant resistance to E action in a number of tissues, including the uterus and mammary gland. In addition, the androgen-sensitive prostate exhibits slightly decreased growth and development, whereas compensatory increases of SRC-2 were observed in brain and testis [12]. We have previously demonstrated that female SRC-1 KO mice have an impaired response to estradiol (E 2 ) treatment following ovariectomy (ovx) [13].…”

Section: Introductionmentioning

confidence: 99%

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The skeletal response to estrogen is impaired in female but not in male steroid receptor coactivator (SRC)-1 knock out mice

Mödder

Sanyal

et al. 2008

Bone

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Estrogen (E) is critical for the maintenance of bone mass in both female and male mice and steroid receptor coactivator (SRC)-1 has been shown to be important for mediating E effects on bone, at least in female mice. In the present study, we defined the skeletal phenotype of male SRC-1 knock out (KO) mice and compared it with their female littermates. Further, to determine the role of SRC-1 in mediating effects of E on bone in male mice, we examined the skeletal effects of gonadectomy (gnx) with or without E replacement in male mice and placed these findings in the context of our previous studies in female SRC-1 KO mice.Analysis of a large group of male (WT, n=67; SRC-1 KO, n=56) and female (WT, n=66; SRC-1 KO, n=70) mice showed a significant decrease in trabecular volumetric bone mineral density (vBMD) in SRC-1 KO mice compared to their WT littermates in both genders (male SRC-1 KO, 275 ± 3 vs WT, 295 ± 3 mg/cm 3 , P<0.001; female SRC-1 KO, 210 ± 2 vs WT, 221 ± 2 mg/cm 3 , P<0.001). Following gnx and E replacement (10 μg/kg/d), we previously demonstrated that SRC-1 KO female mice have a defect in E action in trabecular, but not in cortical bone. In contrast, we now demonstrate that the same dose of E administered to gnx'd male SRC-1 KO mice was sufficient to prevent trabecular bone loss in these mice. For example, in WT female mice, gnx followed by E replacement maintained spine BMD (1.2 ± 3.4% vs baseline) as compared to gnx without E replacement (−12.7 ± 2.6%, P<0.001 vs sham); this effect of E was absent in SRC-1 KO female mice. By contrast, the identical dose of E was equally effective in maintaining spine BMD in E-treated gnx'd male WT (−5.2 ± 5.1% vs baseline) and male SRC-1 KO (−5.4 ± 5.3%) mice, respectively, as compared to gnx'd mice without E treatment (WT, −17.6 ± 2.5%, P=0.02; SRC-1 KO, −28.6 ± 2.6%, P<0.001 vs sham). E treatment was effective in suppressing cancellous bone turnover in both gnx'd WT and SRC-1 KO male mice as determined by significant reductions in osteoblast and osteoclast numbers; however, in female mice, E treatment only suppressed bone turnover in WT but not in SRC-1 KO mice.Collectively, these findings demonstrate that loss of SRC-1 results in trabecular osteopenia in male and female mice, but in contrast to female mice, this is not due to any detectable resistance to E action in trabecular bone in male SRC-1 KO mice.

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Section: Discussionmentioning

confidence: 99%

Section: Generation and Care Of Micementioning

confidence: 99%

Section: Generation and Care Of Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The skeletal response to estrogen is impaired in female but not in male steroid receptor coactivator (SRC)-1 knock out mice

Mödder

Sanyal

et al. 2008

Bone

View full text Add to dashboard Cite

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Estrogen and Progesterone Receptor Signaling and Action

Perrotti

2017

Gene Regulation, Epigenetics and Hormone Signaling

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Carbidopa abrogates L‐dopa decarboxylase coactivation of the androgen receptor and delays prostate tumor progression

Wafa

Cheng

Plaa

et al. 2011

Intl Journal of Cancer

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The androgen receptor (AR) plays a central role in prostate cancer progression to the castration-resistant (CR) lethal state.L-Dopa decarboxylase (DDC) is an AR coactivator that increases in expression with disease progression and is coexpressed with the receptor in prostate adenocarcinoma cells, where it may enhance AR activity. Here, we hypothesize that the DDC enzymatic inhibitor, carbidopa, can suppress DDC-coactivation of AR and retard prostate tumor growth. Treating LNCaP prostate cancer cells with carbidopa in transcriptional assays suppressed the enhanced AR transactivation seen with DDC overexpression and decreased prostate-specific antigen (PSA) mRNA levels. Carbidopa dose-dependently inhibited cell growth and decreased survival in LNCaP cell proliferation and apoptosis assays. The inhibitory effect of carbidopa on DDC-coactivation of AR and cell growth/survival was also observed in PC3 prostate cancer cells (stably expressing AR). In vivo studies demonstrated that serum PSA velocity and tumor growth rates elevated~2-fold in LNCaP xenografts, inducibly overexpressing DDC, were reverted to control levels with carbidopa administration. In castrated mice, treating LNCaP tumors, expressing endogenous DDC, with carbidopa delayed progression to the CR state from 6 to 10 weeks, while serum PSA and tumor growth decreased 4.3-fold and 5.4-fold, respectively. Our study is a first time demonstration that carbidopa can abrogate DDC-coactivation of AR in prostate cancer cells and tumors, decrease serum PSA, reduce tumor growth and delay CR progression. Since carbidopa is clinically approved, it may be readily used as a novel therapeutic strategy to suppress aberrant AR activity and delay prostate cancer progression.Prostate cancer is the most commonly diagnosed nonskin cancer and a leading cause of cancer-related death in men of Western countries. 1,2 Early diagnosed organ-confined prostate tumors are frequently curable by surgery or radiotherapy, while standard treatment for localized advanced and metastatic prostate cancer is androgen-deprivation therapy (ADT). 3,4 The efficacy of ADT is temporary due to progression of disease to a castration-resistant (CR) state, which is incurable with a median life expectancy of 18 months, 5 and only temporary survival extensions are achievable using current docetaxel-based chemotherapy protocols. 6 The androgen receptor (AR) is a central transcription factor that mediates androgenic signals and has been widely studied for its role in the development and progression of prostate cancer to CR disease. 7,8 CR progression is a complex process by which tumor cells gain the ability to survive and proliferate under androgen-deprived conditions. This event in part can involve mechanisms that lead to reactivation of AR through the convergence of alternative growth factor and cytokine signaling pathways, as well as altered activity and expression of AR coregulators. [9][10][11] AR coregulator proteins bind to the receptor and activate (coactivator) or repress (corepressor) AR transcript...

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Partial Hormone Resistance in Mice with Disruption of the Steroid Receptor Coactivator-1 (SRC-1) Gene

Cited by 637 publications

References 21 publications

The skeletal response to estrogen is impaired in female but not in male steroid receptor coactivator (SRC)-1 knock out mice

The skeletal response to estrogen is impaired in female but not in male steroid receptor coactivator (SRC)-1 knock out mice

Estrogen and Progesterone Receptor Signaling and Action

Carbidopa abrogates L‐dopa decarboxylase coactivation of the androgen receptor and delays prostate tumor progression

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