Reversal of antiprogestin resistance and progesterone receptor isoform ratio in acquired resistant mammary carcinomas

Wargon, Victoria; Helguero, Luísa A.; Bolado, Julieta; Rojas, Paulina S.; Novaro, Virginia; Molinolo, Alfredo A.; Lanari, Claudia

doi:10.1007/s10549-008-0150-y

Cited by 30 publications

(68 citation statements)

References 51 publications

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“…www.endocrinology-journals.org (Aupperlee et al 2005, Wargon et al 2008. In addition, in immunofluorescence studies, we observed that both PR isoforms were co-expressed in the same cells.…”

Section: Lanari Et Al: Mpa Breast Cancer Modelsupporting

confidence: 62%

“…It is possible that the increased E 2 levels observed in pregnancy might be counteracting the proliferative effect of Pg. The administration of three different antiprogestins, mifepristone (RU-486), onapristone (ZK 98299) or ZK 230211 (Hoffmann & Sommer 2005), in daily s.c. doses of 6-12 mg/kg body weight, also inhibited tumor growth or induced complete tumor regressions in most of the ductal HI variants growing in BALB/c (Kordon et al 1991, Montecchia et al 1999a, Vanzulli et al 2002, Wargon et al 2008 (Lamb et al 2005b). The antiandrogens hydroxyflutamide and flutamide had no effect (Montecchia et al 1999a).…”

Section: Treatment Responsiveness and Tumor Regressionmentioning

confidence: 94%

“…Cytostasis, apoptosis (Vanzulli et al 2002) or differentiation (Wargon et al 2008) are the hallmarks of tumor regression. The morphological changes of tissue remodeling were preceded by an early increase in p53, p21, and p27 expression.…”

Section: Treatment Responsiveness and Tumor Regressionmentioning

confidence: 99%

“…Both PR-A (83 kDa) and PR-B (115 kDa) were detected in HD and R-PI tumors. PR-A expression was always higher than PR-B (Helguero et al 2003b, Wargon et al 2008) and MPA down-regulated both PR isoforms (Helguero et al 2003b). In UR-PI tumor samples, PR-A expression was almost undetectable (Helguero et al 2003b, Wargon et al 2008.…”

Section: Estrogen and Progesterone Receptorsmentioning

confidence: 99%

“…PR-A expression was always higher than PR-B (Helguero et al 2003b, Wargon et al 2008) and MPA down-regulated both PR isoforms (Helguero et al 2003b). In UR-PI tumor samples, PR-A expression was almost undetectable (Helguero et al 2003b, Wargon et al 2008. In addition, RNase protection assays did not reveal any differences in total mRNA between R-PI and UR-PI tumors.…”

Section: Estrogen and Progesterone Receptorsmentioning

confidence: 99%

See 4 more Smart Citations

The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer

Lanari¹,

Lamb²,

Fabris³

et al. 2009

Endocrine-Related Cancer

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101

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More than 60% of all breast neoplasias are ductal carcinomas expressing estrogen (ER) and progesterone receptors (PR). By contrast, most of the spontaneous, chemically or mouse mammary tumor virus induced tumors, as well as tumors arising in genetically modified mice do not express hormone receptors. We developed a model of breast cancer in which the administration of medroxyprogesterone acetate to BALB/c female mice induces mammary ductal carcinomas with a mean latency of 52 weeks and an incidence of about 80%. These tumors are hormone-dependent (HD), metastatic, express both ER and PR, and are maintained by syngeneic transplants. The model has been further refined to include mammary carcinomas that evolve through different stages of hormone dependence, as well as several hormone-responsive cell lines. In this review, we describe the main features of this tumor model, highlighting the role of PR as a trigger of key signaling pathways mediating tumor growth. In addition, we discuss the relevance of this model in comparison with other presently used breast cancer models pointing out its advantages and limitations and how, this model may be suitable to unravel key questions in breast cancer.

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“…www.endocrinology-journals.org (Aupperlee et al 2005, Wargon et al 2008. In addition, in immunofluorescence studies, we observed that both PR isoforms were co-expressed in the same cells.…”

Section: Lanari Et Al: Mpa Breast Cancer Modelsupporting

confidence: 62%

Section: Treatment Responsiveness and Tumor Regressionmentioning

confidence: 94%

Section: Treatment Responsiveness and Tumor Regressionmentioning

confidence: 99%

Section: Estrogen and Progesterone Receptorsmentioning

confidence: 99%

Section: Estrogen and Progesterone Receptorsmentioning

confidence: 99%

See 3 more Smart Citations

The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer

Lanari¹,

Lamb²,

Fabris³

et al. 2009

Endocrine-Related Cancer

Self Cite

101

View full text Add to dashboard Cite

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Progestin and antiprogestin responsiveness in breast cancer is driven by the PRA/PRB ratio viaAIB1 or SMRT recruitment to the CCND1 and MYC promoters

Wargon

Riggio

Giulianelli

et al. 2014

Intl Journal of Cancer

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There is emerging interest in understanding the role of progesterone receptors (PRs) in breast cancer. The aim of this study was to investigate the proliferative effect of progestins and antiprogestins depending on the relative expression of the A (PRA) and B (PRB) isoforms of PR. In mifepristone (MFP)-resistant murine carcinomas antiprogestin responsiveness was restored by re-expressing PRA using demethylating agents and histone deacetylase inhibitors. Consistently, in two human breast cancer xenograft models, one manipulated to overexpress PRA or PRB (IBH-6 cells), and the other expressing only PRA (T47D-YA) or PRB (T47D-YB), MFP selectively inhibited the growth of PRA-overexpressing tumors and stimulated IBH-6-PRB xenograft growth. Furthermore, in cells with high or equimolar PRA/PRB ratios, which are stimulated to proliferate in vitro by progestins, and are inhibited by MFP, MPA increased the interaction between PR and the coactivator AIB1, and MFP favored the interaction between PR and the corepressor SMRT. In a PRB-dominant context in which MFP stimulates and MPA inhibits cell proliferation, the opposite interactions were observed. Chromatin immunoprecipitation assays in T47D cells in the presence of MPA or MFP confirmed the interactions between PR and the coregulators at the CCND1 and MYC promoters. SMRT downregulation by siRNA abolished the inhibitory effect of MFP on MYC expression and cell proliferation. Our results indicate that antiprogestins are therapeutic tools that selectively inhibit PRA-overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters.

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Inhibition of mammary tumor growth by estrogens: is there a specific role for estrogen receptors alpha and beta?

Soldati

Wargon

Cerliani

et al. 2009

Breast Cancer Res Treat

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To evaluate the extent to which each estrogen receptor (ER) subtype contributes to the stimulation or to the inhibition of mammary tumor growth, we evaluated the effects of specific agonists in MC4-L2 cells, which are stimulated by 17β-estradiol (E(2)), and in mammary carcinomas of the MPA mouse breast cancer model, which are inhibited by E(2). Both express ERα and ERβ. In MC4-L2 cells, 4,4',4"-(4-propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol (PPT; ERα agonist) and (4-hydroxy-phenyl)-propionitrile (DPN; ERβ agonist) stimulated cell proliferation, whereas the opposite occurred in C4-HI primary cultures. The inhibitory effect was associated with a decrease in ERα and cyclin D1 expression and an increase in progesterone receptor (PR) expression as well as in the Bax/Bcl-xl ratio. In vivo, mice carrying C4-HI or 32-2-HI tumors were treated with E(2), PPT or DPN (3 mg/kg/day) or with vehicle. PPT and DPN inhibited tumor size, as did E(2), during the first 72 h. After a few days, DPN-treated tumors started to grow again, while PPT-treated tumors remained quiescent for a longer period of time. A pronounced decrease in the mitotic index and an increase in the apoptotic index was associated with tumor regression. All treated tumors showed: (a) an increase in integrin α6 and Bax expression, (b) an increased stromal laminin redistribution, and (c) a decrease in ERα, Bcl-xl and Bcl-2 expression (P < 0.001). Apoptosis-inducing factor (Aif) expression was increased in DPN-treated tumors, while active caspase 9 was up-regulated in PPT-treated mice, demonstrating the involvement of the intrinsic apoptotic pathway in estrogen-induced regression in this model. In conclusion, our data indicate that although there may be some preferences for activation pathways by the different agonists, the stimulatory or inhibitory effects triggered by estrogens are cell-context dependent rather than ER isoform dependent.

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Reversal of antiprogestin resistance and progesterone receptor isoform ratio in acquired resistant mammary carcinomas

Cited by 30 publications

References 51 publications

The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer

The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer

Progestin and antiprogestin responsiveness in breast cancer is driven by the PRA/PRB ratio viaAIB1 or SMRT recruitment to the CCND1 and MYC promoters

Inhibition of mammary tumor growth by estrogens: is there a specific role for estrogen receptors alpha and beta?

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