Abstract
PurposeSynchronous bilateral breast cancer (SBBC) patients present with cancer in both breasts at the time of diagnosis or within a short time interval. They show higher rates of metastasis and lower overall survival compared to women with unilateral breast cancer. Here we established the first preclinical SBBC model and used molecular imaging to visualize the patterns of metastasis from each primary tumor.ProceduresWe engineered human breast cancer cells to express either Akaluc or Antares2 for bioluminescence imaging (BLI) and tdTomato or zsGreen for ex vivo fluorescence microscopy. Both cell populations were implanted into contralateral mammary fat pads of mice (n=10), and dual-BLI was performed weekly for up to day 29 (n=3), 38 (n=4), or 42 (n=3). Primary tumors and lungs were fixed, and ex vivo fluorescence microscopy was used to analyze the cellular makeup of micrometastases.ResultsSignal from both Antares2 and Akaluc was first detected in the lungs on day 28 and was present in 9 of 10 mice at endpoint. Ex vivo fluorescence microscopy of the lungs revealed that for mice sacrificed on day 38, a significant percentage of micrometastases were composed of cancer cells from both primary tumors (mean 37%; range 27 to 45%), while two mice sacrificed on day 42 showed percentages of 51% and 70%.ConclusionsA high degree of metastatic cross-seeding of cancer cells derived from bilateral tumors may contribute to faster metastatic growth and intratumoral heterogeneity. We posit that our work will help understand treatment resistance and optimal planning of SBBC treatment.
Highlights
IntroductionIn 2015, Jobsen and colleagues reported that the aggressiveness of primary tumors in Synchronous bilateral breast cancer (SBBC) patients does not appear to differ from unilateral breast cancer (UBC) patients, as measured by malignancy grading, mitotic activity index, hormone receptor status, and the presence of positive lymph nodes [2]
Synchronous bilateral breast cancer (SBBC) is defined as the detection of breast cancer in both breasts at the time ofLiu S. et al.: Molecular Imaging of a Novel Mouse Model of Synchronous Bilateral Breast CancerIn 2015, Jobsen and colleagues reported that the aggressiveness of primary tumors in SBBC patients does not appear to differ from unilateral breast cancer (UBC) patients, as measured by malignancy grading, mitotic activity index, hormone receptor status, and the presence of positive lymph nodes [2]
These studies suggest that increased tumor burden and metastasis may explain the lower survival of SBBC patients; little is known about the spread and growth of metastatic cells from each primary tumor over time
Summary
In 2015, Jobsen and colleagues reported that the aggressiveness of primary tumors in SBBC patients does not appear to differ from UBC patients, as measured by malignancy grading, mitotic activity index, hormone receptor status, and the presence of positive lymph nodes [2] They suggested that the worse prognosis of SBBC is due to the combined effect of two tumors, resulting in a higher chance of metastasis. Using a competing risks model, Mejdahl et al found that the combined effect of having two cancers leads to excess mortality and poorer prognosis in comparison with UBC [7] These studies suggest that increased tumor burden and metastasis may explain the lower survival of SBBC patients; little is known about the spread and growth of metastatic cells from each primary tumor over time. Cancer cells implanted into each mammary fat pad were pre-engineered to express a unique set of imaging reporter genes allowing us to distinctly visualize the metastatic fate of cancer cells from each tumor using noninvasive in vivo dual-bioluminescence imaging (BLI) and ex vivo fluorescence microscopy
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