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Background: Obesity 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. Methods: Adult 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. Results: Mice 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. Conclusions: Weight 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. [ABSTRACT FROM AUTHOR]

Epidemiologic studies demonstrate that obesity is associated with an aggressive subtype of breast cancer called basal-like breast cancer (BBC). Using the C3(1)-TAg murine model of BBC, we previously demonstrated that mice displayed an early onset of tumors when fed obesogenic diets in the adult window of susceptibility. Obesity was also shown to elevate mammary gland expression and activation of hepatocyte growth factor (HGF)/c-Met compared to lean controls, a pro-tumorigenic pathway associated with BBC in patients. Epidemiologic studies estimate that weight loss could prevent a large proportion of BBC. We sought to investigate whether weight loss in adulthood prior to tumor onset would protect mice from accelerated tumorigenesis observed in obese mice. Using a life-long model of obesity, C3(1)-TAg mice were weaned onto and maintained on an obesogenic high-fat diet. Obese mice displayed significant elevations in tumor progression, but not latency or burden. Tumor progression was significantly reversed when obese mice were induced to lose weight by switching to a control low-fat diet prior to tumor onset compared to mice maintained on obesogenic diet.We investigated the HGF/c-Met pathway known to regulate tumorigenesis. Importantly, HGF/c-Met expression in normal mammary glands and c-Met in tumors was elevated with obesity and was significantly reversed with weight loss. Changes in tumor growth could not be explained by measures of HGF action including phospho-AKT or phospho-S6. Other mediators associated with oncogenesis such as hyperinsulinemia and a high leptin:adiponectin ratio were elevated by obesity and reduced with weight loss. In sum, weight loss significantly blunted the obesity-responsive protumorigenic HGF/c-Met pathway and improved several metabolic risk factors associated with BBC, which together may have contributed to the dramatic reversal of obesity-driven tumor progression. Future research aims to evaluate the role of obesity and the HGF/c-Met pathway in basal-like breast cancer progression. [ABSTRACT FROM AUTHOR]

Background: Obesity 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., Methods: Adult 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., Results: Mice 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., Conclusions: Weight 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.

Unlabelled: Epidemiologic studies have associated obesity with increased risk of the aggressive basal-like breast cancer (BBC) subtype. Hepatocyte growth factor (HGF) signaling through its receptor, cMET, is elevated in obesity and is a pro-tumorigenic pathway strongly associated with BBC. We previously reported that high fat diet (HFD) elevated HGF, cMET, and phospho-cMET in normal mammary gland, with accelerated tumor development, compared to low fat diet (LFD)-fed lean controls in a murine model of BBC. We also showed that weight loss resulted in a significant reversal of HFD-induced effects on latency and elevation of HGF/cMET signaling in normal mammary and cMET in normal mammary and tumors. Here, we sought to inhibit BBC tumor progression in LFD- and HFD-fed C3(1)-Tag BBC mice using a small molecule cMET inhibitor, and began crizotinib treatment (50 mg/kg body weight by oral gavage) upon identification of the first palpable tumor. We next investigated if administering crizotinib in a window prior to tumor development would inhibit or delay BBC tumorigenesis., Treatment: Crizotinib significantly reduced mean tumor burden by 27.96 and 37.29 %, and mean tumor vascularity by 35.04 and 33.52 %, in our LFD- and HFD-fed C3(1)-Tag BBC mice, respectively., Prevention: Crizotinib significantly accelerated primary tumor progression in both diet groups but had no effect on total tumor progression or total tumor burden. In sum, cMET inhibition by crizotinib limited tumor development and microvascular density in basal-like tumor-bearing mice but did not appear to be an effective preventive agent for BBC.