Conditional mouse models demonstrate oncogene-dependent differences in tumor maintenance and recurrence

Diversity in the pathophysiology of breast cancer frustrates therapeutic progress. We need to understand how mechanisms activated by specific combinations of oncogenes, tumor suppressors, and hormonal signaling pathways govern response to therapy and prognosis. A recent series of investigations conducted by Chodosh and colleagues offers new insights into the similarities and differences between specific oncogenic pathways. Expression of three oncogenes relevant to pathways activated in human breast cancers (c-myc, activated neu and Wnt1) were targeted to murine mammary epithelial cells using the same transgenic tetracycline-responsive conditional gene expression system. While the individual transgenic lines demonstrate similarly high rates of tumor penetrance, rates of oncogene-independent tumor maintenance and recurrence following initial regression are significantly different, and are modifiable by mutations in specific cooperating oncogenes or loss of tumor suppressor gene expression. The experiments make three notable contributions. First, they illustrate that rates of tumor regression and recurrence following initial regression are dependent upon the pathways activated by the initiating oncogene. The experiments also demonstrate that altered expression or mutation of specific cooperating oncogenes or tumor suppressor genes results in different rates of tumor regression and recurrence. Finally, they exemplify the power of conditional mouse models for elucidating how specific molecular mechanisms give rise to the complexity of human cancer

Comparison of mouse mammary gland imaging techniques and applications: Reflectance confocal microscopy, GFP Imaging, and ultrasound

<p>Abstract</p> <p>Background</p> <p>Genetically engineered mouse models of mammary gland cancer enable the <it>in vivo </it>study of molecular mechanisms and signaling during development and cancer pathophysiology. However, traditional whole mount and histological imaging modalities are only applicable to non-viable tissue.</p> <p>Methods</p> <p>We evaluated three techniques that can be quickly applied to living tissue for imaging normal and cancerous mammary gland: reflectance confocal microscopy, green fluorescent protein imaging, and ultrasound imaging.</p> <p>Results</p> <p>In the current study, reflectance confocal imaging offered the highest resolution and was used to optically section mammary ductal structures in the whole mammary gland. Glands remained viable in mammary gland whole organ culture when 1% acetic acid was used as a contrast agent. Our application of using green fluorescent protein expressing transgenic mice in our study allowed for whole mammary gland ductal structures imaging and enabled straightforward serial imaging of mammary gland ducts in whole organ culture to visualize the growth and differentiation process. Ultrasound imaging showed the lowest resolution. However, ultrasound was able to detect mammary preneoplastic lesions 0.2 mm in size and was used to follow cancer growth with serial imaging in living mice.</p> <p>Conclusion</p> <p>In conclusion, each technique enabled serial imaging of living mammary tissue and visualization of growth and development, quickly and with minimal tissue preparation. The use of the higher resolution reflectance confocal and green fluorescent protein imaging techniques and lower resolution ultrasound were complementary.</p

Comparison of mouse mammary gland imaging techniques and applications: Reflectance confocal microscopy, GFP Imaging, and ultrasound-3

D from the incubator to examine alveolar development as visualized with GFP expression. Mammary glands from newborn mice expressing GFP were transplanted into nude mice. and show the newborn mammary gland pre-transplantation GFP and H&E imaging, respectively. Post-transplantation in a non-pregnant nude mouse allows for visualization of ductal development of the transplanted gland as it grows to fill its fat pad whereas transplantation from a pregnant nude mouse causes the transplant to display lobular development characteristic of late pregnancy. GFP images: and (higher power) and and (higher power), Whole mount images: and . Arrows: mammary ducts, thick arrows: lobules, ^: nipple. Magnifications are as indicated.<p><b>Copyright information:</b></p><p>Taken from "Comparison of mouse mammary gland imaging techniques and applications: Reflectance confocal microscopy, GFP Imaging, and ultrasound"</p><p>http://www.biomedcentral.com/1471-2407/8/21</p><p>BMC Cancer 2008;8():21-21.</p><p>Published online 23 Jan 2008</p><p>PMCID:PMC2266934.</p><p></p

Comparison of mouse mammary gland imaging techniques and applications: Reflectance confocal microscopy, GFP Imaging, and ultrasound-6

F tumor at time of necropsy , identify liver metastasis , distinguish between adenocarcinoma and enlarged lymphnodes . Thin white arrow: skin surface, thin black arrow: mitotic figure, thick white arrows: liver metastases, circle and black arrow: dissected metastatic lesion, open white arrow: tumor, *: enlarged lymph node. Scale for all ultrasound images in mm.<p><b>Copyright information:</b></p><p>Taken from "Comparison of mouse mammary gland imaging techniques and applications: Reflectance confocal microscopy, GFP Imaging, and ultrasound"</p><p>http://www.biomedcentral.com/1471-2407/8/21</p><p>BMC Cancer 2008;8():21-21.</p><p>Published online 23 Jan 2008</p><p>PMCID:PMC2266934.</p><p></p

Comparison of mouse mammary gland imaging techniques and applications: Reflectance confocal microscopy, GFP Imaging, and ultrasound-2

E same gland . Mammary tumors appear less bright compared to the mammary ducts and more bright compared to tumor associated blood vessels . Lymph nodes can be highlighted close to brighter mammary ducts . H&E section of a lymph node. Arrows: mammary ducts, ^: mammary tumor, open arrowheads: blood vessels, *: lymph node. Magnifications are as indicated.<p><b>Copyright information:</b></p><p>Taken from "Comparison of mouse mammary gland imaging techniques and applications: Reflectance confocal microscopy, GFP Imaging, and ultrasound"</p><p>http://www.biomedcentral.com/1471-2407/8/21</p><p>BMC Cancer 2008;8():21-21.</p><p>Published online 23 Jan 2008</p><p>PMCID:PMC2266934.</p><p></p

Comparison of mouse mammary gland imaging techniques and applications: Reflectance confocal microscopy, GFP Imaging, and ultrasound-8

Supplemented media immediately . Other glands were put into IPAH culture after RCM imaging which was accomplished by injection with either PBS , 1% acetic acid , 3% acetic acid , or 5% acetic acid . Pre-WOC RCM images display examples of terminal end buds which can be compared to the whole mount (WM) image . Alveolar development in the glands can be compared in post-WOC WM and H&E images. Arrowhead: terminal end bud, arrows: alveolar development, *: lymph node. Magnifications are as indicated.<p><b>Copyright information:</b></p><p>Taken from "Comparison of mouse mammary gland imaging techniques and applications: Reflectance confocal microscopy, GFP Imaging, and ultrasound"</p><p>http://www.biomedcentral.com/1471-2407/8/21</p><p>BMC Cancer 2008;8():21-21.</p><p>Published online 23 Jan 2008</p><p>PMCID:PMC2266934.</p><p></p