Using the Signature Phenotype of Inflammatory Breast Cancer To Study Dormancy and Resistance to Therapeutics.
Adriana D Corben, Clare D'Arcy, Shanu Modi, Gabriela Chiosis, Mary L Alpaugh. Memorial Sloan-Kettering Cancer Center, New York, NY
Background: Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Clinically IBC presents as reddened, edematous breast that is tender to touch. Associated thickening of the skin (peau d' orange) may occur. Clinical features are due to the distinct signature phenotype of extensive intravasation in situ of the lymphatic and blood vessels by tumor emboli. The importance of studying IBC is underlined by the fact that non-IBC primary lesions often recur with the IBC signature phenotype and locally advanced non-IBC successfully treated with neoadjuvant chemotherapy often shows residual carcinoma exclusively in the lymphovasculature.
The human IBC xenograft model, MARY-X, captures the IBC signature phenotype (i.e.tumor emboli grow exclusively within the murine lymphatic and blood vessels). The MARY-X in vitro spheroids and in vivo tumor emboli form on the basis of an, overexpressed, intact E-cadherin/α,β-catenin axis and exhibit a gain in cellular organization. The overexpression of the intact, E-cadherin/α,β-catenin axis is also consistent with human IBC. This provides an in vitro model with tractable in vivo applications.
Design: The major impediment to treating breast cancer patients is the resistance of lymphovascular emboli to therapeutics. To investigate we 1) developed a novel ex vivo approach of fresh tissue sectioning and treatment of breast cancer specimens (n=20) which were analyzed by immunohistochemistry (IHC), 2) IHC analysis of retrospective cases of both IBC (n=10) (with and without neoadjuvant therapy) and non-IBC (n=10) paying particular attention to lymphovascular emboli and 3) validated data in MARY-X, a pre-clinical model of IBC.
Results: Tissue sections (200 μm) of both the primary tumor and associated metastases followed by exposure to therapeutic agents allows for an efficient analysis of treatment response. Tight aggregates (spheroids) of previously loosely-associated infiltrating ductal carcinoma (IDC) nests formed in response to treatment in the primary tumor and metastases and do not undergo apoptosis. Persistent expression or re-expression of E-cadherin was found in resistant side populations.
Conclusions: The findings suggest that the mere formation of tight aggregates due to molecular changes of breast carcinoma can confer resistance to therapy. Identification of these molecular changes offers new therapeutic strategies.
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 27, Tuesday Afternoon