Contributions of Akt1 and GLUT1 to mammary tumor growth, signaling and tumor metabolism

The high rate of glucose transport and glycolysis in tumor cells was described by Otto Warburg nearly eighty years ago. The serine/threonine kinase, Akt, has been demonstrated to be upregulated in a number of cancers and is known to promote cancer cell survival and stimulate glycolysis and plasma membrane localization of the GLUT1 glucose transporter in hematopoietic cells.;Using transgenic mouse models of breast cancer, we evaluated how Akt overexpression alters the tumor latency, signaling, and glucose metabolism profile of mammary tumors in MMTV-c-ErbB2 mice. Bitransgenic MMTV-myr-Akt1, MMTV-c-ErbB2 mice develop mammary tumors twice as fast as MMTV-c-ErbB2 mice. The tumors from bitransgenic mice are characterized by high levels of necrosis, low amounts of apoptosis, attenuated tyrosine signaling downstream of ErbB3 and high rates of lactate secretion as compared to tumors from MMTV-c-ErbB2 mice. The glucose metabolism profile of the bitransgenic tumors is correlated with high expression of GLUT1.;GLUT1 appears to be the most highly expressed glucose transporter in tumors from MMTV-c-ErbB2 mice and cell lines derived from these tumors. Reducing the expression of GLUT1 in mammary carcinoma cells using shRNA reduces glucose metabolism, slows proliferation in culture, reduces growth in soft agar and decreases tumor growth in nude mice. Overexpression of GLUT1 increases glucose transport and accelerates tumor growth in nude mice. GLUT1 plasma membrane localization is inhibited by chemical inhibition of the PI3K/Akt pathway or using shRNA vectors that reduce Akt1 in vitro. Glucose consumption and lactate secretion are also decreased when Akt activity is inhibited chemically or genetically. Conversely, activation of Akt increases glucose consumption and lactate secretion.;Our results suggest that activation of Akt by mutation of PI3K or PTEN in ErbB2 overexpressing tumors may result in resistance to ErbB2-targeted therapies since much of the signaling downstream of ErbB2/ErbB3 is attenuated by Akt activation in transgenic mice. Additionally, activation of Akt appears to increase glucose metabolism in mammary carcinoma. With the re-emergence of glucose metabolism as a hallmark of cancer, our data demonstrating that inhibition of GLUT1 decreases tumor growth and glucose metabolism suggests that therapies targeting metabolism merit further attention.