Progesterone Receptors A and B Differentially Affect the Growth of Estrogen-Dependent Human Breast Tumor Xenografts

Sartorius, Carol A.; Shen, Tianjie; Horwitz, Kathryn B.

doi:10.1023/a:1024031731269

Cited by 76 publications

(78 citation statements)

References 31 publications

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“…5). T47D tumor xenografts grow slowly in the absence of estrogen and in our studies by using male nude mice at 6 wk, the control and Ad.vec injected tumors reached a weight of Ϸ250-300 mg, which agrees with a previous report (39). Although Ad.CMV-E1A or Ad.PEG-E1A inhibited the growth of tumors on the left flank they had some inhibitory effect on tumors on the right side, which was not statistically significant.…”

Section: Resultssupporting

confidence: 93%

Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice

Sarkar

Vozhilla

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

117

185

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Limitations of current viral-based gene therapies for malignant tumors include lack of cancer-specific targeting and insufficient tumor delivery. To ameliorate these problems and develop a truly effective adenovirus gene-based therapy for cancer, we constructed a conditionally replication competent adenovirus (CRCA) manifesting the unique properties of tumor-specific virus replication in combination with production of a cancer-selective cytotoxic cytokine, melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), which embodies potent bystander antitumor activity. Cancer cell selective tropism was ensured by engineering the expression of the adenoviral E1A protein, necessary for viral replication, under the control of a minimal promoter region of progression elevated gene-3 (PEG-3), which functions selectively in diverse cancer cells with minimal activity in normal cells. In the E3 region of this CRCA, we introduced the mda-7/IL-24 gene, thereby mediating robust production of this cytokine as a function of adenovirus replication. Infection of this CRCA (designated Ad.PEG-E1A-mda-7) in normal mammary epithelial cells and breast cancer cells confirmed cancer cell selective adenoviral replication, mda-7/ IL-24 expression, growth inhibition, and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 into human breast cancer xenografts in athymic nude mice completely eradicated not only the primary tumor but also distant tumors (established on the opposite flank of the animal) thereby implementing a cure. This dual cancer-specific targeting strategy provides an effective approach for treating breast and other human neoplasms with the potential for eradicating both primary tumors and metastatic disease. Additionally, these studies support the potential use of mda-7/IL-24 in the therapy of malignant cancers.bystander antitumor activity ͉ conditionally replication competent adenovirus ͉ PEG-Prom ͉ mda-7͞IL-24 ͉ in vivo tumorigenesis

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Section: Resultssupporting

confidence: 93%

Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice

Sarkar

Vozhilla

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

117

185

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“…Breast cancer cells T47D expressing eiPR grew into smaller estrogen-dependent tumors in nude mice than PR-negative cells, and this phenomenon is independent of the PR ligand (37). The effect was PR isoform-selective as tumors expressing PR-A were only half the size of PR-B-expressing tumors.…”

Section: Discussionmentioning

confidence: 96%

A Novel Antiestrogenic Mechanism in Progesterone Receptor-transfected Breast Cancer Cells

Zheng

Bay

et al. 2005

Journal of Biological Chemistry

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The expression of progesterone receptor (PR) is normally estrogen-dependent, and progesterone is only active in target cells following estrogen exposure. This study revealed that the effect of estrogen was markedly disrupted by estrogen-independent expression of PR. Ovarian steroid hormones estrogen and progesterone are essential for the normal growth and development of the breast. The two hormones also play critical roles in the regulation of breast cancer development. It has been established that estrogen stimulates the growth of breast cancer cells both in vivo and in vitro (1-3). Antiestrogens have been the front-line therapy for hormone-dependent breast cancers (4), which are estrogen receptor (ER) 1 -and progesterone receptor (PR)-positive. Nonetheless, antiestrogen-induced remissions are often followed by acquisition of antiestrogen resistance and ultimately disease relapse (5). The acquired resistance is mostly manifested by insensitivity to antiestrogens such as tamoxifen and increased ER activity (6). It has been shown that signaling via the epidermal growth factor receptor and HER-2/neu can activate both ER and the important ER coactivator AIB1 (7). Breast tumors with high levels of AIB1 and HER-2 may be resistant to tamoxifen because of an increase in its estrogen agonist activity. The development of strategies for the effective treatment of tamoxifen-resistant breast cancer is one of the main challenges for breast cancer research. Transfection of PR in estrogen receptor (ER)-Whereas it is established that estrogen stimulates the growth of breast cancer cells, the function of progesterone in breast cancer remains controversial. Progestins were found to stimulate growth, have no effect, or inhibit growth depending on the experimental conditions and the status of hormone receptors (8 -11). This controversy reflects our insufficient understanding of progesterone biology and has hampered effective applications of progestins or antiprogestins in breast cancer treatment.The controversies over the effect of progesterone in breast cancer are due to several complexities in the PR system. One of the complexities is that PR is an estrogen receptor-dependent gene product (12, 13), and the action of progesterone requires priming treatment of estrogen to induce PR. It is conceivable that the prior presence of estrogen may significantly confound assessment of the role of progesterone on growth and other cellular processes in breast cancer cells. On the other hand, the effects of progesterone also depend on a complex interaction between estrogen, progesterone, and their receptors. Studies have demonstrated the suppression of estrogen-stimulated ER activity by agonist-and antagonist-occupied PR (14 -15). However, ER can transmit signals received from the agonist-activated PR to the Src/p21 (ras)/Erk pathway (16), suggesting a synergistic interaction between the ER and PR.Our previous work has shown that estrogen-independent expression of PR by transfection in the ER-and PR-negative breast cancer cells MDA-MB-231, fac...

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“…Of interest, the PR gene is transcribed from two different start sites giving rise to two different receptor isoforms: PR-A and PR-B Progesterone-regulated, anti-tumor genes for ovarian cancer V Syed et al (Giangrande et al, 1997). It has been shown that PR-A and PR-B may exert opposite actions in a target tissue (Cheng et al, 2001;Sartorius et al, 2003;Shao et al, 2003). Hence, it is not a surprise for us to find, in the present study, a unique set of genes (including AFT-3, caveolin-1, DLC-1, and NM23 H2) that are only upregulated by P4 in the OVCA cells but not in the HOSE cells.…”

Section: Discussionmentioning

confidence: 99%

Identification of ATF-3, caveolin-1, DLC-1, and NM23-H2 as putative antitumorigenic, progesterone-regulated genes for ovarian cancer cells by gene profiling

et al. 2005

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Progesterone Receptors A and B Differentially Affect the Growth of Estrogen-Dependent Human Breast Tumor Xenografts

Cited by 76 publications

References 31 publications

Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice

Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice

A Novel Antiestrogenic Mechanism in Progesterone Receptor-transfected Breast Cancer Cells

Identification of ATF-3, caveolin-1, DLC-1, and NM23-H2 as putative antitumorigenic, progesterone-regulated genes for ovarian cancer cells by gene profiling

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