Abstract
BackgroundOverexpression of the bZip transcription factor, ATF3, in basal epithelial cells of transgenic mice under the control of the bovine cytokeratin-5 (CK5) promoter has previously been shown to induce epidermal hyperplasia, hair follicle anomalies and neoplastic lesions of the oral mucosa including squamous cell carcinomas. CK5 is known to be expressed in myoepithelial cells of the mammary gland, suggesting the possibility that transgenic BK5.ATF3 mice may exhibit mammary gland phenotypes.MethodsMammary glands from nulliparous mice in our BK5.ATF3 colony, both non-transgenic and transgenic, were examined for anomalies by histopathology and immunohistochemistry. Nulliparous and biparous female mice were observed for possible mammary tumor development, and suspicious masses were analyzed by histopathology and immunohistochemistry. Human breast tumor samples, as well as normal breast tissue, were similarly analyzed for ATF3 expression.ResultsTransgenic BK5.ATF3 mice expressed nuclear ATF3 in the basal layer of the mammary ductal epithelium, and often developed squamous metaplastic lesions in one or more mammary glands by 25 weeks of age. No progression to malignancy was seen in nulliparous BK5.ATF3 or non-transgenic mice held for 16 months. However, biparous BK5.ATF3 mice developed mammary carcinomas with squamous metaplasia between 6 months and one year of age, reaching an incidence of 67%. Cytokeratin expression in the tumors was profoundly disturbed, including expression of CK5 and CK8 (characteristic of basal and luminal cells, respectively) throughout the epithelial component of the tumors, CK6 (potentially a stem cell marker), CK10 (a marker of interfollicular epidermal differentiation), and mIRSa2 and mIRSa3.1 (markers of the inner root sheath of hair follicles). Immunohistochemical studies indicated that a subset of human breast tumors exhibit high levels of nuclear ATF3 expression.ConclusionOverexpression of ATF3 in CK5-expressing cells of the murine mammary gland results in the development of squamous metaplastic lesions in nulliparous females, and in mammary tumors in biparous mice, suggesting that ATF3 acts as a mammary oncogene. A subset of human breast tumors expresses high levels of ATF3, suggesting that ATF3 may play an oncogenic role in human breast tumorigenesis, and therefore may be useful as either a biomarker or therapeutic target.
Highlights
Overexpression of the bZip transcription factor, ATF3, in basal epithelial cells of transgenic mice under the control of the bovine cytokeratin-5 (CK5) promoter has previously been shown to induce epidermal hyperplasia, hair follicle anomalies and neoplastic lesions of the oral mucosa including squamous cell carcinomas
No ATF3 expression was detectable by IHC in the mammary glands of wild type littermates (Figure 1c,e), the antibody used cross-reacts with ATF3 of both human and murine origin [26]
Immunohistochemistry for estrogen receptor alpha (ERα) (a,b,c) or for ErbB2 (d,e,f) was performed with representative sections from mammary tumors arising in BK5.ATF3 mice (a,d), from a normal appearing mature mammary gland (b), from a mammary tumor that developed in an MMTV.neu transgenic animal (e), or from squamous metaplastic lesions (c, f) that occurred in the mammary glands of nulliparous BK5.ATF3 females
Summary
Overexpression of the bZip transcription factor, ATF3, in basal epithelial cells of transgenic mice under the control of the bovine cytokeratin-5 (CK5) promoter has previously been shown to induce epidermal hyperplasia, hair follicle anomalies and neoplastic lesions of the oral mucosa including squamous cell carcinomas. Most human ductal breast carcinomas express cytokeratin (CK) markers characteristic of the luminal epithelial cell compartment, namely CK8 and CK18 [1] In the past, this led to an overall interest among cancer biologists in cell compartments containing luminal progenitor cells as the possible target populations for carcinogenesis leading to invasive ductal carcinoma (IDC). This led to an overall interest among cancer biologists in cell compartments containing luminal progenitor cells as the possible target populations for carcinogenesis leading to invasive ductal carcinoma (IDC) This is reflected in the extensive development of transgenic mouse models of breast cancer based on promoters thought to be active in such cells, namely the MMTV promoter and pregnancy/ lactation specific promoters [2]. This subset is of particular interest because these tumors tend to be negative for estrogen receptor alpha (ERα), lymph node positive and have a generally poor prognosis [7,8]
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