Plastic Surgery Research Council
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PSRC 60th Annual Meeting

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Developing Tumor-suppressing Autologous Fat Grafts for Breast Cancer Survivors
Jolene Valentin, PhD, Wakako Tsuji, MD, PhD, Chris Chung, BS, Meghan McLaughlin, BS, Kacey Marra, PhD, Vera Donnenberg, PhD, Albert Donnenberg, PhD, J. Peter Rubin, MD.
University of PIttsburgh Medical Center, Pittsburgh, PA, USA.

PURPOSE:
Autologous fat grafting is widely carried out in breast cancer patients, although there is a risk that fat tissues or adipose-derived stem cells (ASCs) may promote breast cancer progression. The incorporation of tumor-suppressing agents into fat grafting may represent an ideal method to reconstruct a natural appearing breast while minimizing local recurrence risk. We studied the differential sensitivities of ASCs and breast cancer cells to anti-breast cancer drugs. We also studied tumor development using estrogen receptor-positive BT-474 and triple-negative MDA-MB-231 breast cancer cell lines in Matrigel, and are currently developing a tumor-forming fat graft model using human adipose tissue.
METHODS:
To study the sensitivity of ASCs when exposed to chemotherapeutic agents, human ASCs were isolated from non-diabetic female patients between 35 and 60 years of age (n=3). BT-474 and MDA-MB-231 breast cancer cell lines were obtained from ATCC. ASCs, BT-474, and MDA-MB-231 were exposed to various concentrations of paclitaxel or 4OH-tamoxifen. Proliferation, viability, and differentiation ability were assessed with CyQuant, MTT, and AdipoRed assays, respectively.
To create a tumor containing graft, viable DAPI-exclusing BT-474 and MDA-MB-231 cancer cells were sorted directly into Matrigel containing 10000 irradiated feeder cells or into lipoaspirate at doses of 10, 100, 1000, 10000, or 100000 cells per injection. 50uL of Matrigel + cells or 300uL of lipoaspirate + cells (A) were injected subcutaneously in NSG immunodeficient mice and sacrificed at 6 weeks. After sacrifice, the grafts were explanted and volumes were measured using gas pycnometry. The grafts were prepared for H&E, cytokeratin, and Ki-67 staining.
RESULTS:
Dose-dependent inhibition was observed for paclitaxel and 4OH tamoxifen in ASCs and both breast cancer cell lines. IC50s of paclitaxel were 15.7, 3.5 and 31.9 µM for BT-474, MDA-MB-231, and ASCs, respectively. IC50s of 4OH tamoxifen were 4.4, 3.2×104 and 28.5µM on BT-474, MDA-MB-231, and ASCs, respectively. 4OH tamoxifen is known to be effective against ER+ cells, such as BT-474. ASCs differentiation into mature adipocytes was not inhibited by anti-breast cancer drugs exposure.
The tumor volumes followed a dose-dependent trend for the Matrigel groups. Histology showed that cancer cells resided in Matrigel and in lipoaspirate grafts containing higher doses of cancer cells at 6 weeks (B). These cells stained positive for human cytokeratin (C) and Ki-67 (D), verifying that cancer cells survived and are proliferative. Results are pending for BT-474 in lipoaspirate grafts.

CONCLUSION:
Our findings suggest that incorporating paclitaxel in fat grafts for breast
reconstruction following primary breast surgery is a viable option for
decreasing the risk of local recurrence. 4OH tamoxifen can also be incorporated in fat grafting with ER-positive breast cancer patients. An in-vivo model employing lipoaspirate and cancer cells to test encapsulated chemotherapeutics is currently being developed with encouraging results. Taken together, incorporating encapsulated chemotherapeutic drugs in autologous fat grafts for breast reconstruction procedures is a feasible therapeutic option for breast cancer survivors.


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