STAT3 is both a transcription activator and an oncogene that is tightly regulated under normal physiological conditions. However, abundant evidence indicates that STAT3 is persistently activated in several cancers, with a crucial position in tumor onset and progression. In addition to its traditional role in cancer cell proliferation, invasion, and migration, STAT3 also promotes cancer through altering gene expression via epigenetic modification, inducing epithelial–mesenchymal transition (EMT) phenotypes in cancer cells, regulating the tumor microenvironment, and promoting cancer stem cells (CSCs) self-renewal and differentiation. STAT3 is regulated not only by the canonical cytokines and growth factors, but also by the G-protein-coupled receptors, cadherin engagement, Toll-like receptors (TLRs), and microRNA (miRNA). Despite the presence of diverse regulators and pivotal biological functions in cancer, no effective therapeutic inventions are available for inhibiting STAT3 and acquiring potent antitumor effects in the clinic. An improved understanding of the complex roles of STAT3 in cancer is required to achieve optimal therapeutic effects.

Transforming growth factor‐beta (TGF‐β) functions as a potent proliferation inhibitor and apoptosis inducer in the early stages of breast cancer, yet promotes cancer aggressiveness in the advanced stages. The dual effect of TGF‐β on cancer development is known as TGF‐β paradox, and the remarkable functional conversion of TGF‐β is a pivotal and controversial phenomenon that has been widely investigated for decades. This phenomenon may be attributed to the cross talk between TGF‐β signaling and other pathways, including EGF receptor (EGFR) signaling during cancer progression. However, the underlying mechanism by which TGF‐β shifts its role from a tumor suppressor to a cancer promoter remains elusive. In this study, TGF‐β is positively correlated with EGFR expression in breast cancer tissues, and a functional linkage is observed between TGF‐β signaling and EGFR transactivation in breast cancer cell lines. TGF‐β promotes the migration and invasion abilities of breast cancer cells, along with the increase in EGFR expression. EGFR is also essential for TGF‐β‐induced enhancement of these abilities of breast cancer cells. Canonical Smad3 signaling and ERK/Sp1 signaling pathways mediate TGF‐β‐induced EGFR upregulation. Hence, our study provided insights into a novel mechanism by which TGF‐β supports breast cancer progression.

Our findings further confirmed the regulatory role of Anxa2 and revealed the direct relationship between Anxa2-Tyr23 phosphorylation and activation of STAT3. Moreover, this study provides novel insights into the function of Anxa2-Tyr23 phosphorylation in signal transduction for further understanding of the mechanism through which Anxa2 promotes the progression of breast cancer.

Our findings suggest that up-regulation of Anxa2 may play an important role in modulating proliferation and invasion of breast cancer MCF-7 cells through regulation of many relevant downstream target genes.

Centrosomal abnormalities have been found in various cancer types. We sought to determine whether centrosomal dysfunctions occur in the atypical ductal hyperplasia (ADH)-carcinoma sequence of breast cancer. As a and g-tubulins are the structural components of centrosomes, we performed real time quantitative polymerase chain reaction (qPCR), in situ hybridization (ISH) and immunnohistochemistry (IHC) to determine the DNA copy levels, messenger RNA (mRNA) expression, and protein expression of a and g-tubulins respectively. g-tubulin staining was used for the localization and quantification of centrosomes. We found that a-tubulin or g-tubulin mRNA was increasingly expressed from normal breast tissue (NBT) to ADH, ductal carcinoma in situ (DCIS), and infiltrative ductal carcinoma (IDC), respectively, with the highest expressions being found in DCIS. The expression profiles of a, γ-tubulin proteins were concordant with that of mRNA, except that the highest expression was found in IDC. Similarly, DNA copies of a, g-tubulins showed a rising tendency, with the highest level for γ-tubulin attained in IDC and that for a-tubulin was found in DCIS. However, there was no significant difference of a, g-tubulin DNA copy levels, mRNA expression, and protein expression between DCIS and IDC. Our results demonstrate that centrosomal aberrations may play key roles in the early stage of breast tumorogenesis. The malignant transformation sequence is probably attributable to the amplification of centrosomal DNA leading to mRNA and protein over-expression of these centrosomal proteins. Furthermore, determination of a, g-tubulins using combined qPCR with ISH may be useful in assisting the diagnosis of premalignant lesions of the breast. (Cancer Sci 2009; 100: 580-587) B reast cancer is the leading cancer among women in Europe and America. In China, epidemiologic studies showed that the incidence of breast cancer has been increasing over the last 20 years, and the standardized rate of the annual incidence has greatly increased from 17 to 24 per 100 000 from 1980 to 2000,(1) with a higher increasing rate for young patients. The role of centrosomes in a wide range of tumor types has been investigated (2,3) and centrosome aberration (supernumerary and structurally altered centrosomes) may play a potentially causative role in malignant progression. Centrosomes are involved in diverse cellular activities, especially in the assembly of the bipolar mitotic spindle and maintaining the genomic fidelity of the daughter cells.(4) It has been hypothesized that dysfunction of centrosomes may lead to chromosomal instability (5,6) and other cellular changes that may be important in the development of malignant tumors.(7) Some researchers found that centrosome defects were present in a significant fraction of precursor lesions, including in situ carcinomas of the uterine cervix, prostate, and female breast by detecting centrosome proteins, pericentrin and γ-tubulin using immunohistochemistry.(8-10) Moreover, supernumerary centrioles (more than four cent...