Constitutive overexpression of Id‐1 in mammary glands of transgenic mice results in precocious and increased formation of terminal end buds, enhanced alveologenesis, delayed involution

Abstract

Inhibitor of differentiation-1 (Id-1) has been shown to play an essential role in cell proliferation, invasion, migration, and anti-apoptosis. However, the effect of Id-1 in mammary gland development remains unknown. Here, we generated MMTV-Id-1 transgenic mice to study the role of Id-1 in mammary gland development. In virgin mice, Id-1 overexpression led to precocious development and delayed regression of terminal end buds (TEBs) compared with wild-type mice. The number of BrdU-positive cells and the expression of Wnt signaling molecules, β-catenin and cyclin D1, which regulate ductal extension and TEB formation in virgin, were statistically higher in Id-1 transgenic mice than in wild-type mice. Id-1 also had an effect on the formation and proliferation of lobuloalveolar structures during early and mid-pregnancy. Id-1 transgenic mice had more lobulated and prominent alveolar budding than wild-type mice and had significantly greater counts of lobuloalveolar structures in early pregnancy. The expression of BrdU, β-catenin, and cyclin D1 was also predominantly increased in Id-1 transgenic mice. Moreover, Id-1 transgenic mice showed delayed involution. Id-1 regulated the expression levels of anti-apoptotic Bcl-2 and pro-apoptotic Bax, and resulted in delay of apoptotic peak during postlactational involution. We also found that Id-1 was able to modulate expression of the regulators of Wnt/β-catenin signaling such as phospho-Akt, BMP2, FGF3, and RAR-β in tubuloalveolar development of mammary glands. Taken together, our results suggest that Id-1 plays a pivotal role in mammary gland development through Wnt signaling-mediated acceleration of precocity and alveologenesis and Bcl-2 family members-mediated delay of involution.

A pooled shRNA screen for regulators of primary mammary stem and progenitor cells identifies roles for Asap1 and Prox1

“…Among deleterious shRNAs were those targeting essential genes such as the TATA binding protein (Tbp), which is required for transcription (Table 1 ). Notably, several known regulators of mammary gland morphogenesis and/or epithelial proliferation, such as Ovol2 [ 25 ] and Id1 [ 26 , 27 ], were found to be significantly depleted (Figure 1 D and Table 1 ). Moreover, basally-expressed transcription factors ( Tcf4 and Lef1 ) that are implicated in mammary stem cell renewal through the Wnt pathway were depleted in the functional screen [ 28 ].…”

Increased expression of Id1 and Id3 promotes tumorigenicity by enhancing angiogenesis and suppressing apoptosis in small cell lung cancer

“…Thus, the greatest increment in the percentage of apoptotic cells was achieved through double knockdown of Id1 and Id3 in N417 cells. It was previously observed that Id proteins could induce apoptosis in some cell types (38-40), but also function as anti-apoptotic molecules in others (41, 42). Our results showed that inhibition of Id1 and Id3 promoted apoptosis of N417 cells in response to cisplatin treatment.…”

MEL-18 loss mediates estrogen receptor–α downregulation and hormone independence

“…After the tumors were dissected, IHC analysis was performed using consecutive sections of tumors from 3 independent xenografted mice as described previously (13,48). The results were scored by multiplying the percentage of positive cells by the staining intensity as described in the IHC staining section.…”