C/EBPδ is a crucial regulator of pro-apoptotic gene expression during mammary gland involution

Abstract

The STAT3 transcription factor is an important initiator of mammary gland involution in the mouse. This work shows that the STAT3 target gene CCAAT/enhancer binding protein delta (C/EBP␦ ␦) is a crucial mediator of proapoptotic gene expression events in mammary epithelial cells. In the absence of C/EBP␦ ␦, involution is delayed, the pro-apoptotic genes encoding p53, BAK, IGFBP5 and SGP2/clusterin are not activated, while the anti-apoptotic genes coding for BFL1 and Cyclin D1 are not repressed. Consequently, p53 targets such as survivin, BRCA1, BRCA2 and BAX are not regulated appropriately and protease activation is delayed. Furthermore, expression of MMP3 and C/EBP␤ ␤ during the second phase of involution is perturbed in the absence of C/EBP␦ ␦. In HC11 cells, C/EBP␦ ␦ alone is sufficient to induce IGFBP5 and SGP2. It also suppresses Cyclin D1 expression and cooperates with p53 to elicit apoptosis. This study places C/EBP␦ ␦ between STAT3 and several pro-and anti-apoptotic genes promoting the physiological cell death response in epithelial cells at the onset of mammary gland involution.

Transcription factor regulatory networks in mammary epithelial development and tumorigenesis

“…Another important transcriptional target of STAT3 was C/EBPd (Thangaraju et al, 2005;Zhang et al, 2007). Like STAT3, germ-line disruption of C/EBPd resulted in a profound defect in mammary gland involution (Thangaraju et al, 2005).…”

“…Like STAT3, germ-line disruption of C/EBPd resulted in a profound defect in mammary gland involution (Thangaraju et al, 2005). Thus, genetic and biochemical analyses suggest that a STAT3-dependent inflammatory cascade is essential for the normal involution of the mammary gland (Pensa et al, 2009).…”

C/EBPδ targets cyclin D1 for proteasome-mediated degradation via induction of CDC27/APC3 expression

“…Gene expression analysis showed that C/EBPδ induction during involution correlated with repression of cyclin D1 expression (12). In vitro, C/EBPδ overexpression in a mouse MEC line accelerated the decline of cyclin D1 expression upon serum withdrawal (6).…”

Nucling, a Novel Apoptosis-associated Protein, Controls Mammary Gland Involution by Regulating NF-κB and STAT3

“…C/EBP␦ is known to be important in the apoptotic response in mammary glands as well as in diminished involution in C/EBP␦-deficient mice (37). STAT3 was previously shown to be activated after weaning and acts as a critical regulator of apoptosis in involution (7,8).…”