Growth inhibition of MCF-7 human breast cancer cells by progesterone is associated with cell differentiation and phosphorylation of Akt protein

Alkhalaf, Moussa; El‐Mowafy, Abdalla M.; Karam, Sawsan H.

doi:10.1097/00008469-200210000-00011

Cited by 23 publications

(24 citation statements)

References 23 publications

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“…Although a slight increase in cell growth was already found after incubation with P4 alone, the presence of E2 resulted in increased proliferation. These findings are in agreement with the literature, which previously demonstrated that P4 in MCF7 cells enhanced primarily differentiation whereas proliferation was mainly caused by E2 [Alkhalaf et al, 2002]. Nevertheless, the gene expression profile of MCF7 cells previously treated with P4 alone comprised genes involved in cell cycle and DNA repair.…”

Section: Discussionsupporting

confidence: 93%

Elucidating progesterone effects in breast cancer: Cross talk with PDGF signaling pathway in smooth muscle cell

Soares

Guerreiro

Botelho

2006

J of Cellular Biochemistry

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Several studies indicate that progesterone exerts relevant effects in breast tissue. However, the exact role of this steroid in breast cancer development and progression has not been elucidated. Here, we show that platelet-derived growth factor (PDGF)-A is one of the progesterone target genes on breast cancer MCF7 and T47D cells. A paracrine role for PDGF-A was investigated, since its receptor expression was down-regulated from breast cancer cells. Progesterone increased PDGF-A protein release as evaluated by Western blotting and ELISA. Medium from Progesterone-treated MCF7 cells resulted in phosphorylation of smooth muscle cells PDGF receptor a. This effect was not observed after treatment with PDGF inhibitor. MCF7 cells-secreted PDGF-A was able to increase smooth muscle cell viability and proliferation and decrease apoptosis, effects that were prevented by the use of a PDGF-A neutralizing antibody. Notably, cell invasion was not influenced by PDGF-A secreted by MCF7 cells. Our results elucidated for the first time the cross talk between progesterone and PDGF signaling pathway. The fact that MCF7-secreted PDGF elicited crucial roles in vascular wall smooth muscle cells, suggested a paracrine pathway for progesterone. Targeting these progesterone-induced processes may provide novel therapeutic strategies for hormone-dependent human breast cancer.

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Section: Discussionsupporting

confidence: 93%

Elucidating progesterone effects in breast cancer: Cross talk with PDGF signaling pathway in smooth muscle cell

Soares

Guerreiro

Botelho

2006

J of Cellular Biochemistry

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“…Depending on growth factors/cytokine-signaling pathways, which are specific to and different in each cell line, the cell fate induced by progesterone may be different: growth inhibition or proliferation. In conditions similar to ours, other studies also indicated that progestininduced growth inhibition coincides with enhancement of differentiation in various mammary cell lines, including T-47D (Kester et al, 1997;Alkhalaf et al, 2002;Lin et al, 2003). In all cases, all these hormonal effects on proliferation and/or differentiation appear to be completely independent of the protective effect of the hormone against radiation-induced apoptosis.…”

Section: Discussionsupporting

confidence: 87%

“…In studies showing that progesterone mediated growth inhibition via apoptosis induction (Formby and Wiley, 1998;Gompel et al, 2000), overall the rate of apoptosis was very low and, more importantly, the hormone was used at a high and nonphysiological concentration. Using physiological ranges of progesterone concentrations (1-100 nM), we and others (Ory et al, 2001;Alkhalaf et al, 2002) showed a significant protective effect of progesterone against apoptosis. Moreover, in standard conditions of culture, we failed to observe any difference in the rate of cell death in unirradiated cells with or without progesterone treatment (Figure 3).…”

Section: Discussionmentioning

confidence: 67%

“…Several reports indicate that progesterone also plays a role in the regulation of cell signaling pathways potentially implicated in the control of the apoptotic process: activation of the PI3/Akt pathway associated with a protection against apoptosis (Alkhalaf et al, 2002), activation of the c-Src/p21/MAP kinase signal transducing pathway (Migliaccio et al, 1998;Lange et al, 1999), and others. Progestins may also regulate p53 in various contexts: progesterone may decrease the expression of p53 in experimental models where it presents a proliferative activity (Hurd et al, 1995), or it may inhibit cell growth and apoptosis via direct upregulation of p53 in ovarian cells (Murdoch and Van Kirk, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Pro- Wiley, 1998, 1999;Kandouz et al, 1999), as well as antiapoptotic effects (Bardon et al, 1987;Alkhalaf et al, 2002) of progesterone and progestin treatment of breast cancer cell lines have been suggested. However, we recently showed that progesterone protected breast cancer cells against serum depletion-induced apoptosis (Ory et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Progesterone prevents radiation-induced apoptosis in breast cancer cells

Varès¹,

Ory²,

Lectard³

et al. 2004

Oncogene

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Sex steroid hormones play an essential role in the control of homeostasis in the mammary gland. Although the involvement of progesterone in cellular proliferation and differentiation is well established, its exact role in the control of cell death still remains unclear. As dysregulation of the apoptotic process plays an important role in the pathogenesis of breast cancer, we investigated the regulation of apoptosis by progesterone in various breast cancer cell lines. Our results show that progesterone treatment protects against radiation-induced apoptosis. This prevention appears to be mediated by the progesterone receptor and is unrelated to p53 status. There is also no correlation with the intrinsic hormonal effect on cell proliferation, as the presence of cells in a particular phase of the cell cycle. Surprisingly, progesterone partly allows bypassing of the irradiation-induced growth arrest in G 2 /M in PgR þ cells, leading to an increase in cell proliferation after irradiation. One consequence of this effect is a higher rate of chromosome damage in these proliferating progesterone-treated cells compared to what is observed in untreated irradiated cells. We propose that progesterone, by inhibiting apoptosis and promoting the proliferation of cells with DNA damage, potentially facilitates the emergence of genetic mutations that may play a role in malignant transformation.

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The activities of progesterone receptor isoform A and B are differentially modulated by their ligands in a gene‐selective manner

Leo

Lin

2007

Intl Journal of Cancer

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It is known that progesterone receptor (PR) isoform A (PR‐A) and isoform B (PR‐B) may mediate different effects of progesterone. The objective of this study was to determine if the functions of PR isoforms also vary in response to different PR modulators (PRM). The effects of 7 synthetic PRM were tested in MDA‐MB‐231 cells engineered to express PR‐A, PR‐B, or both PR isoforms. The effects of progesterone were similar in cells expressing PR‐A or PR‐B in which it inhibited growth and induced focal adhesion. On the other hand, synthetic PRM modulated the activity of the PR isoforms differently. RU486, CDB4124, 17α‐hydroxy CDB4124 and VA2914 exerted agonist activities on cell growth and adhesion via PR‐B. Via PR‐A, however, these compounds displayed agonist effect on cell growth but induced stellate morphology which was distinct from the agonist's effect. Their dual properties via PR‐A were also displayed at the gene expression level: the compounds acted as agonists on cell cycle genes but exhibited antagonistic effect on cell adhesion genes. Introduction of ERα by adenoviral vector to these cells did not change PR‐A or PR‐B mediated effect of PRM radically, but it causes significant cell rounding and modified the magnitudes of the responses to PRM. The findings suggest that the activities of PR isoforms may be modulated by different PRM through gene‐specific regulatory mechanisms. This raises an interesting possibility that PRM may be designed to be PR isoform and cellular pathway selective to achieve targeted therapy in breast cancer. © 2007 Wiley‐Liss, Inc.

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Growth inhibition of MCF-7 human breast cancer cells by progesterone is associated with cell differentiation and phosphorylation of Akt protein

Cited by 23 publications

References 23 publications

Elucidating progesterone effects in breast cancer: Cross talk with PDGF signaling pathway in smooth muscle cell

Elucidating progesterone effects in breast cancer: Cross talk with PDGF signaling pathway in smooth muscle cell

Progesterone prevents radiation-induced apoptosis in breast cancer cells

The activities of progesterone receptor isoform A and B are differentially modulated by their ligands in a gene‐selective manner

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