Abstract P4-16-01: A novel approach to breast cancer prevention: Exploiting autologous fat grafting for the local delivery of cancer therapeutics
Authors: Munster PN , Chen S , Thomas S , Thurn KT , Raha P , Foster R , Irvin C , Sbitany H 
Published: August 2014

Abstract
Background: Breast cancer remains a considerable health concern, despite major advances in the treatment and prevention of breast cancer. Inhibition of estrogen receptor signaling is one of the most effective therapies for patients with hormone receptor positive breast cancer. However, even after chemotherapy and hormonal therapy, local recurrence occurs frequently, and undesirable side effects lead to drug discontinuation in an estimated 40% of patients on adjuvant therapy.
Autologous fat transfer is an emerging therapy used in breast reconstruction to restore surgical deformities after lumpectomy, or to rebuild the breast following mastectomy. This is an attractive option for both radiated and non-radiated patients, as complication rates in both groups are exceedingly low. Fat is injected into the breast or surgical cavity to maximize its contact with local vascularized tissue, to promote re-vascularization and survival of the adipose tissue. Thus, fat cells are injected throughout the tissue surrounding the surgical margin. We hypothesize that harvested adipose tissue can be loaded with a lipophilic drug prior to its re-injection into the breast cavity and its surrounding tissue. With the release of drug from the transplanted adipose tissue over time, the local concentration of an anti-estrogen within the breast parenchyma would be increased and systemic toxicity may be minimized.
Method: Human adipose tissue was acquired from patients undergoing liposuction for autologous grafting. Tissue was washed with warm PBS, divided into 0.5 mL aliquots, and incubated in complete DMEM (10% FBS) containing increasing concentrations of 4-OH tamoxifen (0, 10, 20, or 40 uM) or fulvestrant (0, 0.1, 0.5, or 1.0 uM) for 12 hours. Following incubation, adipose tissue was washed thoroughly and co-cultured with MCF7 cells for 96 hours. Adipocyte co-cultured MCF7 were then collected and evaluated for proliferation, viability and effects on estrogen receptor signaling and compared to MCF7 directly exposed to anti-estrogens.
Results: When co-culturing tamoxifen- or fulvestrant-loaded human adipocytes with MCF7 breast cancer cells in vitro, we observed a dose-dependent reduction in cell proliferation (tamoxifen, 60% reduction; fulvestrant, 40% reduction) and viability (20%), comparable to directly drugged media. Examination of the molecular response to fulvestrant demonstrated a dose dependent down regulation of ER protein expression and activity (e.g. PgR and Cyclin D1). Currently, we are characterizing the pharmacokinetics of anti-estrogen uptake and release in both in vitro and in vivo.
Summary: Our preliminary data suggest that co-culturing human adipocytes with an anti-estrogen results in tumor growth inhibition and abrogation of estrogen receptor signaling. Human adipocytes used to fill the tumor bed cavity or mastectomy pocket could therefore be used as a vehicle to deliver anti-estrogens to residual tumor cells and prevent tumor regrowth. This method may be a novel technology to combine reconstructive surgery and anti-cancer therapy and prevention.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-16-01.