Intracellular Location of the SOX9 Protein in Breast Disease

Abstract

SOX9, an important factor for testis determination and chondrogenesis, was previously detected in the nucleus of testicular sertoli cells and chondrocytes but was found in only a subset of ovarian sertoli cell tumors, carcinoid tumors, and endometrioid carcinomas, and occasionally only in the cytoplasm of those cells. SOX9 has also been detected in metaplastic carcinomas of the breast exhibiting chondroid differentiation so it became of interest to examine SOX9 in other breast carcinomas and normal breast. Normal breast lobules were studied immunohistochemically for SOX9 along with examples of metaplastic breast carcinoma exhibiting chondroid differentiation, lobular neoplasia (ALH/LCIS), invasive lobular carcinomas, and ductal carcinomas (invasive and in situ). SOX9 was identified solely in the nucleus in over 90% of the normal breast epithelial cells examined. In 10 of 12 breast carcinomas exhibiting chondroid metaplasia, and in 15 of 16 invasive lobular carcinomas, SOX9 was present primarily in the nucleus much like that seen in normal breast epithelium. In 14 of 20 invasive ductal carcinomas, however, it was missing or identified mainly in the cytoplasm of the malignant cells. The functional importance of SOX9 in the breast is unknown although transcription factors involved with the development of certain tissues may have similar capabilities in other organs. The retention of SOX9 in the nucleus of metaplastic or lobular carcinomas could indicate some functional expression of this protein in these tumors with an even more compelling reason why it is often restricted to the cytoplasm, or missing, in ductal carcinomas of the breast.

Immunohistochemical expression of SOX9 protein in immature, mature, and neoplastic canine Sertoli cells

“…According to Chakravarty et al (2011), cytoplasmic SOX9 in breast cancer is associated with invasive and metastatic breast carcinomas and it is related to increased cell proliferation. Similarly, in two thirds of ductal breast lesions, SOX9 protein was located in the cytoplasm and not in the nucleus [34]. Moreover, cytoplasmic and membranous SOX9 staining has been demonstrated in "borderline" ovarian tumors and not in well-differentiated ones [33].…”

“…The dynamic subcellular redistribution of SOX9 protein in the gonads at the time of sexual differentiation has been described both in humans and mice [8][9] demonstrating that SOX9 is able to shuttle between the nucleus and the cytoplasm, hypothesizing the existence of a nuclear export signal triggering male-specific sexual differentiation [32]. In human medicine, no data regarding testicular neoplasm and SOX9 expression are present, but this marker has been employed on other neoplastic tissues (mammary gland and ovaries) revealing interesting results in a subset of cases, such as cytoplasmic and/or membranous labeling [27,33,34].…”

An image-based multi-label human protein subcellular localization predictor (iLocator) reveals protein mislocalizations in cancer tissues

“…In contrast, a reduction of cyclin D1 exported from the nucleus can lead to overexpression of this protein in the nucleus, and the inactivation of retinoblastoma, which is a tumor-suppressing protein (Gladden and Diehl, 2005). Other such multiple-location shuttling proteins associated with cancers include p53, BRCA1, SOX9 and APC (Bratthauer and Vinh, 2009;Fabbro and Henderson, 2003). Detecting these changes requires accurate multi-label predictors.…”