Abstract
BackgroundInflammatory breast cancer (IBC) is the most lethal form of locally advanced breast cancer. We found concordant and consistent alterations of two genes in 90% of IBC tumors when compared with stage-matched non-IBC tumors: overexpression of RhoC guanosine triphosphatase and loss of WNT-1 induced secreted protein 3 (WISP3). Further work revealed that RhoC is a transforming oncogene for human mammary epithelial (HME) cells. Despite the aggressiveness of the RhoC-driven phenotype, it does not quantitatively reach that of the true IBC tumors. We have demonstrated that WISP3 has tumor growth and angiogenesis inhibitory functions in IBC. We proposed that RhoC and WISP3 cooperate in the development of IBC.MethodsUsing an antisense approach, we blocked WISP3 expression in HME cells. Cellular proliferation and growth were determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay and anchorage-independent growth in a soft agar assay. Vascular endothelial growth factor (VEGF) was measured in conditioned medium by enzyme-linked immunosorbent assay.ResultsAntisense inhibition of WISP3 in HME cells increased RhoC mRNA levels and resulted in an increase in cellular proliferation, anchorage-independent growth and VEGF levels in the conditioned medium. Conversely, restoration of WISP3 expression in the highly malignant IBC cell line SUM149 was able to decrease the expression of RhoC protein.ConclusionWISP3 modulates RhoC expression in HME cells and in the IBC cell line SUM149. This provides further evidence that these two genes act in concert to give rise to the highly aggressive IBC phenotype. We propose a model of this interaction as a starting point for further investigations.
Highlights
Inflammatory breast cancer (IBC) is the most lethal form of locally advanced breast cancer and accounts for approximately 6% of new breast cancer cases annually in the United States [1,2]
Inhibition of WNT-1 induced secreted protein 3 (WISP3) increases RhoC mRNA levels in immortalized human mammary epithelial (HME) cells and induces proliferation, anchorage-independent growth, and vascular endothelial growth factor (VEGF) production To study the effects of inhibition of WISP3 expression on the phenotype of HME cells, we established clones of HME cells stably transfected with antisense WISP3 constructs (HME/AS WISP3)
Inhibition of WISP3 expression in HME cells resulted in increased expression of RhoC transcript in comparison with HME cells transfected with the control empty vector (Fig. 1)
Summary
Inflammatory breast cancer (IBC) is the most lethal form of locally advanced breast cancer and accounts for approximately 6% of new breast cancer cases annually in the United States [1,2]. One salient feature of IBC that is observed in tissue sections is that cancer cells form emboli that spread through the dermal lymphatics. The dermatotropism of IBC is believed to be responsible for the clinical signs and symptoms and probably enables effective dissemination to distant sites [2]. These observations lead us to conclude that IBC is highly invasive and that it is capable of metastases from its inception. We proposed that RhoC and WISP3 cooperate in the development of IBC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
