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TReP-132 Is a Novel Progesterone Receptor Coactivator Required for the Inhibition of Breast Cancer Cell Growth and Enhancement of Differentiation by Progesterone

Florence Gizard,^1,2,3, Romain Robillard,^1,2,3, Barbara Gross,^1,2,3 Olivier Barbier,^1,2,3 Françoise Révillion,⁴ Jean-Philippe Peyrat,⁴ Gérard Torpier,^1,2,3 Dean W. Hum,^5* and Bart Staels^1,2,3*

Institut Pasteur de Lille, Département d'Athérosclérose, Lille, F-59019 France,¹ INSERM, U545, Lille, F-59019 France,² Université de Lille 2, Lille, F-59006 France,³ Laboratoire d'Oncologie Moléculaire Humaine, Centre Oscar Lambret, Lille, France,⁴ Genfit, Parc Eurasanté, Loos, F-59120 France⁵

Received 22 February 2006/ Returned for modification 27 March 2006/ Accepted 24 July 2006

The sex steroid progesterone is essential for the proliferation and differentiation of the mammary gland epithelium during pregnancy. In relation to this, in vitro studies using breast carcinoma T47D cells have demonstrated a biphasic progesterone response, consisting of an initial proliferative burst followed by a sustained growth arrest. However, the transcriptional factors acting with the progesterone receptor (PR) to mediate the progesterone effects on mammary cell growth and differentiation remain to be determined. Recently, it has been demonstrated that the transcriptional regulating protein of 132 kDa (TReP-132), initially identified as a regulator of steroidogenesis, is also a cell growth suppressor. Similar to progesterone-bound PR, TReP-132 acts by inducing the gene expression of the G₁ cyclin-dependent kinase inhibitors p21^WAF1/Cip1 (p21) and p27^Kip1 (p27). The putative interaction between TReP-132 and progesterone pathways in mammary cells was therefore analyzed in the present study. Our results show that TReP-132 interacts in vitro and in T47D cells with progesterone-activated PR. TReP-132 synergizes with progesterone-bound PR to trans activate the p21 and p27 gene promoters at proximal Sp1-binding sites. Moreover, TReP-132 overexpression and knockdown, respectively, increased or prevented the induction of p21 and p27 gene expression by progesterone. As a consequence, TReP-132 knockdown also resulted in the loss of the inhibitory effects of progesterone on pRB phosphorylation, G₁/S cell cycle progression, and cell proliferation. Furthermore, the knockdown of TReP-132 expression also prevented the induction of both early and terminal markers of breast cell differentiation which had been previously identified as progesterone target genes. As well, the progesterone-induced accumulation of lipid vacuoles was inhibited in the TReP-132-depleted cells. Finally, TReP-132 gene expression levels increased following progesterone treatment, indicating the existence of a positive auto-regulatory loop between PR and TReP-132. Taken together, these data identify TReP-132 as a coactivator of PR mediating the growth-inhibitory and differentiation effects of progesterone on breast cancer cells.

F.G. and R.R. contributed equally to the study.

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