title: Tip30 deletion in MMTV-Neu mice leads to enhanced EGFR signaling and development of estrogen receptor-positive and progesterone receptor-negative mammary tumors.
abstract: Estrogen receptor-positive and progesterone receptor-negative (ER+/PR-) breast cancers account for 15% to 25% of all human breast cancers and display more aggressive malignant characteristics than ER+/PR+ cancers. However, the molecular mechanism underlying development of ER+/PR- breast cancers still remains elusive. We show here that Tip30 deletion dramatically accelerated the onset of mammary tumors in the MMTV-Neu mouse model of breast cancer. The mammary tumors arising in Tip30(-/-)/MMTV-Neu mice were exclusively ER+/PR-. The growth of these ER+/PR- tumors depends not only on estrogen but also on progesterone despite the absence of detectable PR. Tip30 is predominantly expressed in ER+ mammary epithelial cells, and its deletion leads to an increase in the number of phospho-ERα-positive cells in mammary glands and accelerated activation of Akt in MMTV-Neu mice. Moreover, we found that Tip30 regulates the EGFR pathway through controlling endocytic downregulation of EGFR protein level and signaling. Together, these findings suggest a novel mechanism in which loss of Tip30 cooperates with Neu activation to enhance the activation of Akt signaling, leading to the development of ER+/PR- mammary tumors.
authors.affiliation: Department of Biomedical and Integrative Physiology, College of Human Medicine, Michigan State University, 3193 Biomedical and Physical Sciences Building, East Lansing, MI 48824-3320, USA.
authors.forename: Chengliang
authors.initials: C
authors.lastname: Zhang
authors.forename: Mikito
authors.initials: M
authors.lastname: Mori
authors.forename: Shenglan
authors.initials: S
authors.lastname: Gao
authors.forename: Aimin
authors.initials: A
authors.lastname: Li
authors.forename: Isamu
authors.initials: I
authors.lastname: Hoshino
authors.forename: Mark D
authors.initials: MD
authors.lastname: Aupperlee
authors.forename: Sandra Z
authors.initials: SZ
authors.lastname: Haslam
authors.forename: Hua
authors.initials: H
authors.lastname: Xiao
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D018734:Genes, erbB-2; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis* / Q000378:metabolism; D011980:Receptors, Progesterone / Q000096:biosynthesis* / Q000378:metabolism; D012097:Repressor Proteins / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D012097:Repressor Proteins; C525546:Tip30 protein, mouse; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt