Adipose cells promote resistance of breast cancer cells to trastuzumab-mediated antibody-dependent cellular cytotoxicity

Abstract

IntroductionTrastuzumab has been used in the treatment of human epidermal growth factor receptor 2 (HER2)-expressing breast cancer, but its efficacy is limited by de novo or acquired resistance. Although many mechanisms have been proposed to explain resistance to trastuzumab, little is known concerning the role of the tumor microenvironment. Given the importance of antibody-dependent cellular cytotoxicity (ADCC) in the antitumor effect of trastuzumab and the abundance of adipose tissue in the breast, we investigated the impact of adipocytes on ADCC.MethodsWe set up a coculture system to study the effect of adipocytes on ADCC in vitro. The results were validated in vivo in a mouse xenograft model.ResultsWe found that adipocytes, as well as preadipocytes, inhibited trastuzumab-mediated ADCC in HER2-expressing breast cancer cells via the secretion of soluble factors. The inhibition of ADCC was not due to titration or degradation of the antibody. We found that adipose cells decreased the secretion of interferon-γ by natural killer cells, but did not alter natural killer cells’ cytotoxicity. Preincubation of breast cancer cells with the conditioned medium derived from adipocytes reduced the sensitivity of cancer cells to ADCC. Using a transcriptomic approach, we found that cancer cells undergo major modifications when exposed to adipocyte-conditioned medium. Importantly, breast tumors grafted next to lipomas displayed resistance to trastuzumab in mouse xenograft models.ConclusionsCollectively, our findings underline the importance of adipose tissue in the resistance to trastuzumab and suggest that approaches targeting the adipocyte–cancer cell crosstalk may help sensitize cancer cells to trastuzumab-based therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0569-0) contains supplementary material, which is available to authorized users.

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“…SV40TAg mice on the HAFD did not gain significantly more weight compared with the mice on a regular diet, suggesting that critical changes affecting tumor growth occur in the mammary glands independently of systemic obesity . It has been also suggested that an inflammatory state exists in animal models that is associated with excess systemic adiposity resulting from high fat diet consumption, which then promotes mammary cancer progression . The connection between high fat diet/obesity and breast cancer has been attributed in part to adipose tissue dysfunction, which may occur locally within mammary fat pads, even in the absence of systemic increased adiposity.…”

Targeted therapies in breast cancer: New challenges to fight against resistance

“…A reduced antitumor effect was observed in mice which had tumors in close proximity to a lipoma, while in another group of mice which had tumors located distant to the lipoma, the trastuzumab anti-tumor effects were enhanced. The inhibition of antitumor activity was enhanced when the adipocytes were in hypoxic conditions, these factors might suggest a link between patient obesity and development of trastuzumab resistance mechanisms[76]. …”

HIV Persistence in Adipose Tissue Reservoirs

“…Adipocytes cross-talk with tumor cells to promote growth and metastases, and further enhance chemotherapeutic resistance by impairing mechanisms of tumor cell killing and sequestering drugs. For example, trastuzumab is a critical antibody-based chemotherapeutic against breast cancer which mediates tumor cell killing by natural killer cells and ADCC mechanisms, and adipocytes suppress such tumor cell killing by secreting factors that impair NK cell functions [102]. Additionally, daunorubicin is another important chemotherapeutic for leukemias and adipocytes enhance survival of acute lymphoblastic leukemia cells by secreting factors which protect the tumor cells from oxidative stress, as well as by accumulating and inactivating significant amounts of daunorubicin [103, 104].…”