An Essential Role of Maspin in Embryogenesis and Tumor Suppression

Abstract

Maspin (SerpinB5) is an epithelial-specific tumor suppressor gene product that displays context-dependent cellular functions. Maspin-deficient mouse models created to date have not definitively established maspin functions critical for cancer suppression. In this study, we generated a mouse strain in which exon 4 of the Maspin gene was deleted, confirming its essential role in development but also enabling a breeding scheme to bypass embryonic lethality. Phenotypic characterization of this viable strain established that maspin deficiency was associated with a reduction in maximum body weight and a variety of context-dependent epithelial abnormalities. Specifically, maspin-deficient mice exhibited pulmonary adenocarcinoma, myoepithelial hyperplasia of the mammary gland, hyperplasia of luminal cells of dorsolateral and anterior prostate, and atrophy of luminal cells of ventral prostate and stratum spinosum of epidermis. These cancer phenotypes were accompanied by increased inflammatory stroma. These mice also displayed the autoimmune disorder alopecia aerate. Overall, our findings defined context-specific tumor suppressor roles for maspin in a clinically relevant model to study maspin functions in cancer and other pathologies.

An Essential Role of Maspin in Embryogenesis and Tumor Suppression—Response

“…We are writing to respond to Drs. James C. Whisstock (JCW) and Philip I. Bird (PIB) who submitted a letter (1) to Cancer Research (CR) regarding a recent publication by Dzinic and colleagues in CR entitled "An Essential Role of Maspin in Embryogenesis and Tumor Suppression" (2).…”

“…2A (2), viable animals with all three genotypes according to Mendelian distribution were produced. Thus, the results of Dzinic and colleagues (2) in part reproduced the results of Drs. JCW and PIB (4).…”

The Opportunity of Precision Medicine for Breast Cancer With Context‐Sensitive Tumor Suppressor Maspin

“…The signature maspin expression in myoepithelial cells may be directly activated by p63 [Popnikolov et al, ]. Accumulated evidence indicates that maspin has distinct roles in the outer myoepithelial layer and in the luminal epithelial cells of the mammary gland branching ductal network [Sternlicht et al, ; Jones et al, ; Espinosa de los Monteros et al, ; Dzinic et al, ].…”

“…According to a phylogenetic analysis, maspin is one of the most evolutionarily conserved serpins [Benarafa and Remold‐O'Donnell, ]. In development, maspin plays an essential role in embryogenesis, and a critical role in epithelial differentiation [Dzinic et al, ]. Although, the biological functions of maspin may differ in distinct types of normal epithelial cells, accumulated clinical and preclinical evidence demonstrate several common tumor suppressive properties of maspin as it undergoes differential expression in multiple types of carcinomas including breast cancer.…”

“…Normal mammary myoepithelial cells that express maspin at a high level and predominantly in the nucleus are widely known to resist malignant transformation [Pandey et al, ]. When the Maspin gene is conditionally knocked out in oogenesis by Zp3‐Cre mediated recombination, the virgin mammary glands of the resulting animals display myoepithelial hyperplasia and increased mammary duct branching while the luminal epithelial cell morphology remains largely unchanged [Dzinic et al, ]. In early stages of breast carcinogenesis, the myoepithelial layer is believed to play a critical tumor suppressive role, which is attributed, at least in part, to the high level of maspin secretion.…”