Tazarotene-Induced Gene 3 Is Suppressed in Basal Cell Carcinomas and Reversed In Vivo by Tazarotene Application

Abstract

Basal cell carcinomas are the most common form of skin cancer. Tazarotene is a retinoic acid receptor selective retinoid that upregulates a tumor suppressor, tazarotene-induced gene 3 (TIG-3), in keratinocytes and psoriasis. Expression of TIG-3 in basal cell carcinomas was studied in an opened-label pilot biomarker study of 22 patients with basal cell carcinomas who applied tazarotene 0.1% gel for up to 12 wk prior to excision. Nineteen paired baseline and treated specimens were compared using immunohistochemistry and in situ hybridization. Compared to overlying normal epidermis, TIG-3 protein and mRNA were decreased in 14 and 18 of 19 basal cell carcinomas (74% and 95%), respectively (p < 0.001). Tazarotene treatment was associated with increased TIG-3 protein and mRNA expression in basal cell carcinomas compared to baseline levels (p < or = 0.001 and p = 0.028, respectively). Sixty percent of basal cell carcinomas treated with tazarotene decreased in size by at least 25%. Ten of 19 lesions improved histologically, including three complete responses. There was a correlation between the increased expression of TIG-3 protein and histologic improvement (p = 0.020), suggesting that suppression of TIG-3 may underlie the development of basal cell carcinomas. This association suggests that reversal of TIG-3 expression may help to explain the mechanism of retinoid action in epidermal differentiation and chemoprevention.

Topical Tazarotene Chemoprevention Reduces Basal Cell Carcinoma Number and Size in Ptch1 +/− Mice Exposed to Ultraviolet or Ionizing Radiation

“…Thus, TIG3 up-regulation by tazarotene may be required for the inhibition of BCC formation. In support of this, a recent study correlated the efficacy of topical tazarotene against human BCCs with induction of TIG3 expression (34). Also, tazarotene causes growth suppression in retinoid-responsive breast cancer cell lines by upregulating TIG3 (32), whereas in prostate cancer, another tazaroteneinduced gene, TIG1 (induced also in keratinocytes), is deleted, and transfection of TIG1 into prostate cancer cell lines reduces their invasiveness in vitro and their growth in vivo (35,36).…”

Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells

“…HRSL3 was found to suppress growth of rodent and human carcinoma cells in vitro and in vivo and is downregulated in breast, ovary and kidney carcinomas (Husmann et al, 1998;Sers et al, 1997;Sers et al, 2002). The RARRES3 protein is suppressed in many human tumors such as ovarian (Lotz et al, 2005), gastric (Huang et al, 2000), colorectal (Huang et al, 2000;Shyu et al, 2003) and head and neck tumors (Higuchi et al, 2003), in psoriatic lesions and in basal cell carcinomas (Duvic et al, 2000;Duvic et al, 2003). It can activate type I transglutaminase by an unknown mechanism thereby inducing terminal differentiation (Sturniolo et al, 2003).…”

TIG3 Interaction at the Centrosome Alters Microtubule Distribution and Centrosome Function

“…The Nterminal domain encodes NCEHFV and LRYG sequence motifs that are conserved among family members (Anantharaman and Aravind, 2003). Consistent with a role in reducing cell survival, the level of TIG3 is reduced in hyperproliferative keratinocytes that are present in psoriatic lesions and skin tumor cells (Duvic et al, 1997;Duvic et al, 2000;Duvic et al, 2003). Treating psoriatic lesions with vitamin-A-related ligands increases the level of TIG3, which is associated with reduced disease severity (Duvic et al, 1997;Duvic et al, 2000;Duvic et al, 2003).…”