Antisense oligonucleotides targeting the progesterone receptor inhibit hormone-independent breast cancer growth in mice

Lamb, Caroline A.; Helguero, Luísa A.; Giulianelli, Sebastián; Soldati, Rocío; Vanzulli, Silvia I.; Molinolo, Alfredo A.; Lanari, Claudia

doi:10.1186/bcr1345

Cited by 29 publications

(30 citation statements)

References 42 publications

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“…In our tumor model, we have already demonstrated that the antiprogestin onapristone was as effective as RU-486 at inducing regression of 59-2-HI, 32-2-HI and C7-2-HI tumors [36] and, furthermore, that antisense oligonucleotides of PR inhibited 32-2-HI tumor growth [39]. In the present study, we have also shown that the new antiprogestin ZK 230211 is as effective as RU-486 in inducing tumor regression.…”

Section: Discussionsupporting

confidence: 61%

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

Wargon

Helguero

Bolado

et al. 2008

Breast Cancer Res Treat

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To explore mechanisms related to hormone resistance, three resistant variants of the MPA mouse breast cancer tumor model with low levels of progesterone receptor (PR) isoform A (PR-A)/high PR-B expression were developed by prolonged selective pressure with antiprogestins. The resistant phenotype of one tumor line was reversed spontaneously after several consecutive passages in syngeneic BALB/c mice or by 17-beta-estradiol or tamoxifen treatment, and this reversion was significantly associated with an increase in PR-A expression. The responsive parental tumors disclosed low activation of ERK and high activation of AKT; resistant tumors on the other hand, showed the opposite, and this was associated with a higher metastatic potential, that did not revert. This study shows for the first time in vivo a relationship between PR isoform expression and antiprogestin responsiveness, demonstrating that, whereas acquired resistance may be reversed, changes in kinase activation and metastatic potential are unidirectional associated with tumor progression.

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Section: Discussionsupporting

confidence: 61%

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

Wargon

Helguero

Bolado

et al. 2008

Breast Cancer Res Treat

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“…32-2-HI is the HI variant derived from 32-HD [36]. Both tumors express ERa, ERb, and PRs and regress with antiprogestin or estrogen treatment [42,43].…”

Section: Animalsmentioning

confidence: 99%

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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“…Histopathological analyses of the uterus and vagina indicated an estrogenic effect, probably due to low estrogen levels (Michna et al 1989). Similarly, we demonstrated that BALB/c mice, treated with antisense PR (asPR) oligonucleotides, showed continuous estrous (Lamb et al 2005).…”

Section: Micementioning

confidence: 66%

“…The role of the PR in the antiprogestin-induced effect was confirmed using asPR oligonucleotides to knockdown PR expression in vivo (Lamb et al 2005). These tumors may also regress with E 2 treatment (0.5-5 mg pellets), almost as well as with antiprogestin treatment.…”

Section: Contributions Of the Mpa Murine Breast Cancer Modelmentioning

confidence: 81%

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Antiprogestins in breast cancer treatment: are we ready?

Lanari

Wargon²,

Rojas³

et al. 2012

Endocrine-Related Cancer

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Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide. It is accepted that breast cancer is not a single disease, but instead constitutes a spectrum of tumor subtypes with distinct cellular origins, somatic changes, and etiologies. Molecular gene expression studies have divided breast cancer into several categories, i.e. basallike, ErbB2 enriched, normal breast-like (adipose tissue gene signature), luminal subtype A, luminal subtype B, and claudin-low. Chances are that as our knowledge increases, each of these types will also be subclassified. More than 66% of breast carcinomas express estrogen receptor alpha (ERa) and respond to antiestrogen therapies. Most of these ERC tumors also express progesterone receptors (PRs), the expression of which has been considered as a reliable marker of a functional ER. In this paper we will review the evidence suggesting that PRs are valid targets for breast cancer therapy. Experimental data suggest that both PR isoforms (A and B) have different roles in breast cancer cell growth, and antiprogestins have already been clinically used in patients who have failed to other therapies. We hypothesize that antiprogestin therapy may be suitable for patients with high levels of PR-A. This paper will go over the experimental evidence of our laboratory and others supporting the use of antiprogestins in selected breast cancer patients.

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Antisense oligonucleotides targeting the progesterone receptor inhibit hormone-independent breast cancer growth in mice

Cited by 29 publications

References 42 publications

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

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

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

Antiprogestins in breast cancer treatment: are we ready?

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