title: Tamoxifen selects for breast cancer cells with mammosphere forming capacity and increased growth rate.
abstract: Using the M05 mouse mammary tumor model and the MCF-7 cell line, we investigated the effect of tamoxifen treatment on the fraction of breast cancer cells with self-renewing capacity both in vitro and in vivo. We found that pretreatment with 4-OH-tamoxifen leads to an increase in cells with the ability of forming mammospheres that express lower levels of ER-α and increased expression of transcription factors associated with pluripotency. Moreover, exposure on plastic to 4-OH-tamoxifen by itself leads to an upregulation of these transcription factors. M05 tumors grown in mice treated with tamoxifen have a higher percentage of cells with self-renewing capacity and this proportion is conserved when tumors are passaged to nontreated mice. Furthermore, interruption of tamoxifen leads to increased tumor growth compared to tumors grown in mice that were never exposed to the antiestrogen. In addition, these tumors are characterized by a higher number of CD24(l)CD29(h) cells compared to tumors grown in nontreated mice. Treatment in vitro with 4-OH-tamoxifen for 5 days leads to a long lasting increase in the proportion of cells with self-renewing capacity even after 1 month of growth in the absence of the antiestrogen. Finally, we compared the mammosphere forming capacity of hormone dependent and independent passages of the M05 tumor and found that hormone independence is associated to an increase in cells with self-renewing capacity. Our results support previous findings that suggest that endocrine treatment selects for cells with stem cell properties.
authors.affiliation: Research Area, Área Investigación, Instituto de Oncología "Angel H. Roffo", Avda. San Martín 5481, C1417DTB, Buenos Aires, Argentina.
authors.forename: Diego
authors.initials: D
authors.lastname: Raffo
authors.forename: Damian E
authors.initials: DE
authors.lastname: Berardi
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Pontiggia
authors.forename: Laura
authors.initials: L
authors.lastname: Todaro
authors.forename: Elisa Bal
authors.initials: EB
authors.lastname: de Kier Joffé
authors.forename: Marina
authors.initials: M
authors.lastname: Simian
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D051927:CD24 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D019012:Integrin beta1 / Q000378:metabolism; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D010641:Phenotype; D018874:Spheroids, Cellular / Q000187:drug effects*; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; D051927:CD24 Antigen; D019012:Integrin beta1; D013629:Tamoxifen