[Show abstract][Hide abstract] ABSTRACT: Hedgehog (Hh) signaling is a regulator of salivary gland morphogenesis, but its role in postnatal glands has only recently begun to be addressed. To examine the effects of deregulated Hh signaling in the salivary gland, we expressed the Hh effector protein GLI1, in salivary epithelial cells using both cytokeratin 5 and mouse mammary tumor virus (MMTV) transgenic systems. Ectopic pathway activation resulted in restrained acinar differentiation, formation of cystic lesions, and prominent appearance of ductal structures. Moreover, induced expression of GLI1 aids the formation of hyperplastic lesions, which closely resemble GLI1-induced changes in murine skin and mammary glands, suggesting that GLI1 targets cells with similar characteristics in different tissues. Furthermore, GLI1-expressing salivary epithelial cells are actively dividing, and GLI1-induced lesions are proliferative, an incident accompanied by enhanced expression of the Hh target genes, cyclin D1, and Snail. GLI1-induced salivary lesions regress after transgene withdrawal and become histologically normalized. Taken together, our data reveal the ability of GLI1 to modulate salivary acinar differentiation and to promote proliferation of ductal epithelial cells.
American Journal Of Pathology 09/2011; 179(5):2569-79. DOI:10.1016/j.ajpath.2011.07.033 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A diverse set of cellular defects, presumably elicited by multiple genetic alterations, underlies cancer development. Aberrant Hedgehog (Hh) signaling has recently been implicated in the development and maintenance of breast cancer. However, evidence conclusively showing that activated Hh signaling can induce mammary tumors is lacking. We now show that transgenic expression of the Hh effector protein GLI1 under the regulation of the mouse mammary tumor virus promoter, expressed in the mouse mammary gland, is associated with the appearance of hyperplastic lesions, defective terminal end buds, and tumor development. The GLI1-induced tumors are histologically heterogeneous and involve the expansion of a population of epithelial cells expressing the progenitor cell markers keratin 6 and Bmi-1. Moreover, tumor cells express genes involved in proliferation, cell survival, and metastasis. GLI1-induced tumors do not fully regress following transgene deinduction, indicating that some tumors develop and are maintained autonomously, independent of sustained transgenic GLI1 expression. The data strongly support a role of Hh/GLI signaling in breast cancer development and suggest that inhibition of this signaling pathway represents a new therapeutic opportunity for limiting tumorigenesis and early tumorigenic progression.
Cancer Research 06/2009; 69(11):4810-7. DOI:10.1158/0008-5472.CAN-08-3938 · 9.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Breast cancer is the most common cause of cancer death among women worldwide. In order to improve the treatment of this disease, a more complete understanding of its biological basis is necessary. Since the Hedgehog (Hh) pathway was recently found to be required for growth and propagation of a number of different cancers, we discuss here the possible involvement of this pathway in the normal biology and development of cancer in the mammary gland. The use of mouse mammary cancer models has assisted the process of dissecting the mechanisms behind Hh-driven mammary tumour formation and growth. Based on recent studies, we conclude that the inhibition of Hh signalling in breast tumours may interfere with the maintenance of a putative cancer stem cell compartment and the abnormal stimulation of tumour stroma. Therefore, the components of the Hh signalling cascade may provide a set of drug targets, which could be implemented into novel combinatorial strategies for the treatment of breast cancer.
[Show abstract][Hide abstract] ABSTRACT: The Hedgehog signaling pathway regulates the development and function of numerous tissues and when mis-regulated causes tumorigenesis. To assess the role of a deregulated Hedgehog signaling pathway in the mammary gland we targeted the expression of the Hedgehog effector protein, GLI1, to mammary epithelial cells using a bigenic inducible system. A constitutively active Hedgehog signaling pathway resulted with 100% penetrance in an undifferentiated mammary lobuloalveolar network during pregnancy. GLI1-expressing transgenic females were unable to lactate and milk protein gene expression was essentially absent. The inability to lactate was permanent and independent of continued GLI1 transgene expression. An increased expression of the GLI1 response gene Snail coupled to reduced expression of E-cadherin and STAT5 in the transgenic mammary gland provides a likely molecular explanation, underlying the observed phenotypic changes. In addition, remodeling of the mammary gland after parturition was impaired and expression of GLI1 was associated with accumulation of cellular debris in the mammary ducts during involution, indicating a defect in the clearance of dead cells. Areas with highly proliferative epithelial cells were observed in mammary glands with induced expression of GLI1. Within such areas an increased frequency of cells expressing nuclear Cyclin D1 was observed. Taken together the data support the notion that correct regulation of Hedgehog signaling within the epithelial cell compartment is critical for pregnancy-induced mammary gland development and remodeling.