The Utility of ATF3 in Cutaneous Epithelial Neoplasms
Crystal L Rose, Jonathan L Curry, Carlos A Torres Cabala, Nitin Chakravarti, Victor G Prieto, Michael T Tetzlaff. University of Texas MD Anderson Cancer Center, Houston, TX
Background: The histopathologic distinction between benign and malignant cutaneous keratinocytic proliferations can present a diagnostic challenge. Activating Transcription Factor 3 (ATF3) is a potential biomarker which may aid in the segregation of these lesions. ATF3 is a member of the ATF/cAMP response element-binding (CREB) transcription factor family, which functions as a downstream effector in the ras-mitogen activated protein kinase (MAPK) signaling cascade. ATF3 is typically induced by cellular stressors such as hypoxia and DNA damage; in addition its overexpression has been described in ductal carcinoma of the breast, prostatic adenocarcinoma, Hodgkin lymphoma and invasive squamous cell carcinoma (SCC). Furthermore, enforced overexpression of ATF3 in the oral mucosa of mice results in the development of squamous cell carcinomas. These findings suggest an oncogenic role for ATF3 in these tumor types, and we hypothesize that ATF3 expression may be a specific marker of SCC. Therefore, its expression could be used to distinguish SCCs from basal cell carcinomas (BCC) as well as benign keratinocytic lesions.
Design: In a pilot study, we characterized ATF3 expression by immunohistochemistry in a series of moderately differentiated cutaneous SCCs (n = 8), nodular BCCs (n = 8) and BCCs with squamous differentiation (n = 8). The percentage of cells with nuclear and/or nucleolar expression of ATF3 was scored (1 = <10% of cells, 2=10-50% of cells, and 3= >50% of cells) by at least two separate dermatopathologists.
Results: We demonstrate strong, nuclear and/or nucleolar expression of ATF3 in all cases of SCC (score=2 in 2/8 cases. 25%; score=3 in 6/8 cases, 75%) but either absent or focal, weak nucleolar ATF3 expression in nodular BCCs (score=2 in 2/8 cases, 25%). Interestingly, we identify strong nuclear and/or nucleolar positivity in BCCs containing areas of squamous differentiation (score=2 in 3/8 cases, 37.5%; score=3 in 1/8 cases, 12.5%).
Conclusions: We conclude that ATF3 distinguishes invasive SCCs from nodular BCCs and is a marker for squamous differentiation in invasive cutaneous carcinomas. In future experiments, we will interrogate whether the expression of ATF3 delineates SCCs and actinic keratoses from other benign keratinocytic proliferations and can therefore function as a useful and specific biomarker in equivocal cases.
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 109, Tuesday Morning