Involvement of Mitogen-Activated Protein Kinase Kinase 6 in Breast Tumorigenesis.

Abstract

MKK6 expression analysis has been reported in various primary tumors, like esophagus, stomach, colon and prostate cancers but its significance in primary breast tumor patients remains unclear. We investigated the expression of MKK6 in cancer tissues through immunoblotting and immunofluorescence techniques in 25 resected cases of human breast carcinomas. Increased MKK6 protein expression was observed in 56% (14 ⁄ 25) of breast cancer cases. These results indicate that the upregulated expression of MKK6 in cancer tissues has significant role in tumor progression and the clinical prognosis of patients with primary breast carcinoma. …………………………………………………………………………………………………….... Introduction:-Breast cancer is one of the most common cancers with more than 1.3 million cases and 0.45 million deaths each year worldwide [1]. It is the number one cancer amongst females accounting for 5.59% of total cancers in females of Kashmir valley only [2]. Breast cancer development involves progression through chain of intermediate processes, which starts with ductal hyper-proliferation, followed by subsequent progression to carcinoma in situ, invasive carcinoma, and finally into metastatic disease [3]. Studies have shown that metastasis is a series of diverse events, generally known as a metastatic cascade. These steps include fleeing of malignant cells from the site of primary tumor, propagation and shifting to a discontinuous secondary site(s), and lastly, the survival and growth into clinically detectable metastases, a process termed metastatic colonization [4]. In order to significantly augment our understanding of the metastatic process and to identify the specific targets for cancer therapy we need to single out the proteins and signaling pathways necessary for regulation of metastasis. In various cancers many proteins show differential expression and regulation [5][6][7]. One such protein is mitogen-activated protein kinase 6 (which from now onwards will be referred to as MKK6). MKK6 belongs to the mitogen-activated protein (MAP) kinase super family and has a role in both apoptosis [8,9] as well as proliferation [10]. MKK6 has been implicated in regulating tumorigenesis. MKK6 has been shown to play contradictory roles in suppressing metastatic colonization in human ovarian carcinoma [11] on other hand it has been shown to be up-regulated in prostate cancers [12]. As of now, very little is known about the regulation of expression of MKK6 in the cell [13]. MKK6 activates downstream all the isoforms of p38 MAPK [14]. P38α has been implicated in regulating cancer progression, by regulating invasion, inflammation and angiogenesis which are key oncogenic steps in tumorogenesis [15][16][17].