Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-1920-3) contains supplementary material, which is available to authorized users.
Highlights
Basal-like breast cancer (BBC) accounts for 15–20 % of total breast cancers, with a higher prevalence in young and minority women such as African Americans and Hispanics (Carey et al 2006; Boyle 2012)
Using primary murine fibroblasts isolated from mammary glands or tumors, we further reported that obesity increased hepatocyte growth factor (HGF) production by mammary gland normal- and cancer-associated fibroblasts (NAF and CAF) (Sundaram et al 2013a)
HGF is the only known ligand for cMET, and the HGF/cMET signaling pathway has long been studied in normal development, ductal morphogenesis (Garner et al 2011), invasive breast cancer (Tuck et al 1996; Yamashita et al 1994; Elliott et al 2002; Wang et al 1994; Jin et al 1997; Beviglia et al 1997), and invasive biology of several other cancers due to its angiogenic, mitogenic, and morphogenic effects (Stella et al 2005; Sam et al 2007)
Summary
Basal-like breast cancer (BBC) accounts for 15–20 % of total breast cancers, with a higher prevalence in young and minority women such as African Americans and Hispanics (Carey et al 2006; Boyle 2012). Marking the first work in preclinical models paralleling human epidemiologic BBC findings, we used C3(1)-TAg mice, a unique genetically engineered mouse model (GEMM) of spontaneous BBC, to demonstrate that high fat diet (HFD)-induced obesity accelerated onset of tumor development and increased tumor aggressiveness as compared to low fat diet (LFD)-fed lean controls (Sundaram et al 2013a). Through signaling inhibition via an HGF blocking antibody, we showed that obese CAF-induced epithelial cell migration occurred in an HGF-dependent mechanism. HFD-induced elevation of HGF/cMET signaling in normal mammary gland and cMET in tumors was significantly reversed with weight loss in C3(1)-Tag mice, with a concomitant and complete reversal of HFD-driven tumor progression (Sundaram et al 2014b)
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