Weight loss reduces basal-like breast cancer through kinome reprogramming

Abstract

BackgroundObesity is associated with an aggressive subtype of breast cancer called basal-like breast cancer (BBC). BBC has no targeted therapies, making the need for mechanistic insight urgent. Reducing adiposity in adulthood can lower incidence of BBC in humans. Thus, this study investigated whether a dietary intervention to reduce adiposity prior to tumor onset would reverse HFD-induced BBC.MethodsAdult C3(1)-Tag mice were fed a low or high fat diet (LFD, HFD), and an obese group initially exposed to HFD was then switched to LFD to induce weight loss. A subset of mice was sacrificed prior to average tumor latency to examine unaffected mammary gland. Latency, tumor burden and progression was evaluated for effect of diet exposure. Physiologic, histology and proteomic analysis was undertaken to determine mechanisms regulating obesity and weight loss in BBC risk. Statistical analysis included Kaplan–Meier and log rank analysis to investigate latency. Student’s t tests or ANOVA compared variables.ResultsMice that lost weight displayed significantly delayed latency compared to mice fed HFD, with latency matching those on LFD. Plasma leptin concentrations significantly increased with adiposity, were reduced to control levels with weight loss, and negatively correlated with tumor latency. HFD increased atypical ductal hyperplasia and ductal carcinoma in situ in mammary gland isolated prior to mean latency—a phenomenon that was lost in mice induced to lose weight. Importantly, kinome analysis revealed that weight loss reversed HFD-upregulated activity of PKC-α, PKD1, PKA, and MEK3 and increased AMPKα activity in unaffected mammary glands isolated prior to tumor latency.ConclusionsWeight loss prior to tumor onset protected against the effects of HFD on latency and pre-neoplastic lesions including atypical ductal hyperplasia and DCIS. Using innovative kinomics, multiple kinases upstream of MAPK/P38α were demonstrated to be activated by HFD-induced weight gain and reversed with weight loss, providing novel targets in obesity-associated BBC. Thus, the HFD-exposed microenvironment that promoted early tumor onset was reprogrammed by weight loss and the restoration of a lean phenotype. Our work contributes to an understanding of underlying mechanisms associated with tumor and normal mammary changes that occur with weight loss.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-016-0300-y) contains supplementary material, which is available to authorized users.

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

“…They showed that obese mice display the greatest TNBC aggression compared to tumors in lean mice with early onset (reduced latency) or increased progression and activation of certain kinases and oncogenic signaling cascades in an obesity-specific manner. [112][113][114][115][116] Formerly, obese mice that lost weight through diet alteration display reversal of that obesity-driven progression to lean levels in this spontaneous GEMM of basal-like TNBC, 113,116 as well as ongoing studies using orthotopically transplanted syngenetic models (data not shown).…”

“…As the role of obesity in TNBC is established in epidemiologic studies 11,[140][141][142][143][144] and experimental findings are formed from our laboratory and others, 79,99,[112][113][114][115][116][134][135][136][137][138][139] it is essential to identify novel underlying mechanisms associated with obesity, weight gain, or weight loss that impact TNBC outcomes. Inflammation associated with obesity is one well-studied consequence that influences risk, tumor outcomes, and therapeutic efficacy.…”

Contribution of Adipose Tissue to Development of Cancer

“…Our lab has demonstrated that inhibition of the HGF receptor, cMET, via the small molecule kinase inhibitor crizotinib significantly reduced tumor burden and tumor vascularity in both lean and obese C3(1)-TAg mice (74). Reversal of high fat diet-induced elevation of HGF/cMET expression in both normal mammary gland and tumors was also observed with weight loss, which significantly blunted the effects of obesity on both pre-neoplastic lesion formation (316) and tumor progression (377) (Fig. 16).…”

Adipocytes and Macrophages Interplay in the Orchestration of Tumor Microenvironment: New Implications in Cancer Progression

“…These interventions could effectively prevent atypical ductal hyperplasia and ductal carcinoma in situ to the points observed in healthy mice. In the same study, the weight loss caused decreased activity of several kinases, which, in turn, caused abrogation of the MAPK pathway, which is related to tumor proliferation ( 115 ). Another study set out to explore this connection, studying breast cancer cells with overexpression of the HER-2 protein treated with trastuzumab, particularly regarding its ADCC mechanism, that is, the antibody-dependent cellular cytotoxicity.…”