Rb deletion in mouse mammary progenitors induces luminal-B or basal-like/EMT tumor subtypes depending on p53 status

Zhe Jiang; Tao Deng; Jones, Robert; Huiqin Li; Herschkowitz, Jason I.; Liu, Jeff C.; Weigman, Victor J.; Ming-Sound Tsao; Lane, Timothy F.; Perou, Charles M.; Zacksenhaus, Eldad; Jiang, Zhe; Deng, Tao; Li, Huiqin; Tsao, Ming-Sound
September 2010
Journal of Clinical Investigation;Sep2010, Vol. 120 Issue 9, p3296
Academic Journal
journal article
Breast cancer is a highly heterogeneous disease, with several different subtypes being characterized by distinct histology, gene expression patterns, and genetic alterations. The tumor suppressor gene retinoblastoma 1 (RB1) is frequently lost in both luminal-B and triple-negative tumor (TNT; i.e., estrogen receptor-, progesterone receptor-, and human epidermal growth factor receptor 2-negative) breast cancer subtypes. However, a causal role for RB1 loss in different subtypes remains undefined. Here we report that deletion of Rb alone or together with its relative p107 in mouse mammary stem/bipotent progenitor cells induced focal acinar hyperplasia with squamous metaplasia. These lesions progressed into histologically diverse, transplantable mammary tumors with features of either luminal-B or TNT subtypes. The TNTs included basal-like tumors as well as tumors that exhibited epithelial-to-mesenchymal transition (EMT). The EMT-type tumors and a subset of the basal-like tumors, but not luminal-B-like tumors, expressed mutant forms of the tumor suppressor p53. Accordingly, targeted deletion of both Rb and p53 in stem/bipotent progenitors led to histologically uniform, aggressive, EMT-type tumors. Reintroduction of Rb into these tumor cells suppressed growth in vitro and tumor formation in vivo. These results establish a causal role for Rb loss in breast cancer in mice and demonstrate that cooperating oncogenic events, such as mutations in p53, dictate tumor subtype after Rb inactivation.


Related Articles

  • Targeting TACE-dependent EGFR ligand shedding in breast cancer. Kenny, Paraic A.; Bissell, Mina J. // Journal of Clinical Investigation;Feb2007, Vol. 117 Issue 2, p337 

    The ability to proliferate independently of signals from other cell types is a fundamental characteristic of tumor cells. Using a 3D culture model of human breast cancer progression, we have delineated a protease-dependent autocrine loop that provides an oncogenic stimulus in the absence of...

  • Tumor escape in a Wnt1-dependent mouse breast cancer model is enabled by p19Arf/p53 pathway lesions but not p16 Ink4a loss. Debies, Michael T.; Gestl, Shelley A.; Mathers, Jessica L.; Mikse, Oliver R.; Leonard, Travis L.; Moody, Susan E.; Chodosh, Lewis A.; Cardiff, Robert D.; Gunther, Edward J. // Journal of Clinical Investigation;Jan2008, Vol. 118 Issue 1, p51 

    Breast cancers frequently progress or relapse during targeted therapy, but the molecular mechanisms that enable escape remain poorly understood. We elucidated genetic determinants underlying tumor escape in a transgenic mouse model of Wnt pathway-driven breast cancer, wherein targeted therapy is...

  • PHF6 mutations in adult acute myeloid leukemia. Van Vlierberghe, P.; Patel, J.; Abdel-Wahab, O.; Lobry, C.; Hedvat, C. V.; Balbin, M.; Nicolas, C.; Payer, A. R.; Fernandez, H. F.; Tallman, M. S.; Paietta, E.; Melnick, A.; Vandenberghe, P.; Speleman, F.; Aifantis, I.; Cools, J.; Levine, R.; Ferrando, A. // Leukemia (08876924);Jan2011, Vol. 25 Issue 1, p130 

    Loss of function mutations and deletions encompassing the plant homeodomain finger 6 (PHF6) gene are present in about 20% of T-cell acute lymphoblastic leukemias (ALLs). Here, we report the identification of recurrent mutations in PHF6 in 10/353 adult acute myeloid leukemias (AMLs). Genetic...

  • The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice. Bongers, Gerold; Maussang, David; Muniz, Luciana R.; Noriega, Vanessa M.; Fraile-Ramos, Alberto; Barker, Nick; Marchesi, Federica; Thirunarayanan, Nanthakumar; Vischer, Henry F.; Lihui Qin; Mayer, Lloyd; Harpaz, Noam; Leurs, Rob; Furtado, Glaucia C.; Clevers, Hans; Tortorella, Domenico; Smit, Martine J.; Lira, Sergio A.; Qin, Lihui // Journal of Clinical Investigation;Nov2010, Vol. 120 Issue 11, p3969 

    US28 is a constitutively active chemokine receptor encoded by CMV (also referred to as human herpesvirus 5), a highly prevalent human virus that infects a broad spectrum of cells, including intestinal epithelial cells (IECs). To study the role of US28 in vivo, we created transgenic mice (VS28...

  • Loss of Nix in Pdx1-deficient mice prevents apoptotic and necrotic β cell death and diabetes. Fujimoto, Kei; Ford, Eric L.; Hung Tran; Wice, Burton M.; Crosby, Seth D.; Dorn II, Gerald W.; Polonsky, Kenneth S.; Tran, Hung; Dorn, Gerald W 2nd // Journal of Clinical Investigation;Nov2010, Vol. 120 Issue 11, p4031 

    Mutations in pancreatic duodenal homeobox (PDX1) are linked to human type 2 diabetes and maturity-onset diabetes of the young type 4. Consistent with this, Pdx1-haploinsufficient mice develop diabetes. Both apoptosis and necrosis of β cells are mechanistically implicated in diabetes in these...

  • Immune protection of nonhuman primates against Ebola virus with single low-dose adenovirus vectors encoding modified GPs. Sullivan, Nancy J.; Geisbert, Thomas W.; Geisbert, Joan B.; Shedlock, Devon J.; Ling Xu; Lamoreaux, Laurie; Custers, Jerome H. H. V.; Popernack, Paul M.; Zhi-Yong Yang; Pau, Maria G.; Roederer, Mario; Koup, Richard A.; Goudsmit, Jaap; Jahrling, Peter B.; Nabel, Gary J.; Xu, Ling; Yang, Zhi-Yong // PLoS Medicine;Jun2006, Vol. 3 Issue 6, pe177 

    Background: Ebola virus causes a hemorrhagic fever syndrome that is associated with high mortality in humans. In the absence of effective therapies for Ebola virus infection, the development of a vaccine becomes an important strategy to contain outbreaks. Immunization with DNA...

  • Mouse ES cell-derived cardiac precursor cells are multipotent and facilitate identification of novel cardiac genes. Christoforou, Nicolas; Miller, Ronald A.; Hill, Christine M.; Jie, Chunfa C.; McCallion, Andrew S.; Gearhart, John D. // Journal of Clinical Investigation;Mar2008, Vol. 118 Issue 3, p894 

    Although the differentiation of ES cells to cardiomyocytes has been firmly established, the extent to which corresponding cardiac precursor cells can contribute to other cardiac populations remains unclear. To determine the molecular and cellular characteristics of cardiac-fated populations...

  • Src: a potential target for the treatment of triple-negative breast cancer. Tryfonopoulos, D.; Walsh, S.; Collins, D. M.; Flanagan, L.; Quinn, C.; Corkery, B.; McDermott, E. W.; Evoy, D.; Pierce, A.; O’Donovan, N.; Crown, J.; Duffy, M. J. // Annals of Oncology;Oct2011, Vol. 22 Issue 10, p2234 

    Background: Triple-negative breast cancers lack expression of estrogen and progesterone receptors and overexpression of human epidermal growth factor receptor 2 (HER2). Unlike other subgroups of patients with breast cancer, targeted therapy is currently unavailable for these patients. The aim of...

  • KLF6-SV1 overexpression accelerates human and mouse prostate cancer progression and metastasis. Narla, Goutham; DiFeo, Analisa; Fernandez, Yolanda; Dhanasekaran, Saravana; Fei Huang; Sangodkar, Jaya; Hod, Eldad; Leake, Devin; Friedman, Scott L.; Hall, Simon J.; Chinnaiyan, Arul M.; Gerald, William L.; Rubin, Mark A.; Martignetti, John A.; Huang, Fei // Journal of Clinical Investigation;Aug2008, Vol. 118 Issue 8, p2711 

    Metastatic prostate cancer (PCa) is one of the leading causes of death from cancer in men. The molecular mechanisms underlying the transition from localized tumor to hormone-refractory metastatic PCa remain largely unknown, and their identification is key for predicting prognosis and targeted...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics