title: Altered TGF-α/β signaling drives cooperation between breast cancer cell populations.
abstract: The role of tumor heterogeneity in regulating disease progression is poorly understood. We hypothesized that interactions between subpopulations of cancer cells can affect the progression of tumors selecting for a more aggressive phenotype. We developed an in vivo assay based on the immortalized nontumorigenic breast cell line MCF10A and its Ras-transformed derivatives AT1 (mildly tumorigenic) and CA1d (highly tumorigenic). CA1d cells outcompeted MCF10A, forming invasive tumors. AT1 grafts were approximately 1% the size of CA1d tumors when initiated using identical cell numbers. In contrast, CA1d/AT1 mixed tumors were larger than tumors composed of AT1 alone (100-fold) or CA1d (3-fold), suggesting cooperation in tumor growth. One of the mechanisms whereby CA1d and AT1 were found to cooperate was by modulation of TGF-α and TGF-β signaling. Both of these molecules were sufficient to induce changes in AT1 proliferative potential in vitro. Reisolation of AT1 tumor-derived (AT1-TD) cells from these mixed tumors revealed that AT1-TDcells grew in vivo, forming tumors as large as tumorigenic CA1d cells. Cooperation between subpopulations of cancer epithelium is an understudied mechanism of tumor growth and invasion that may have implications on tumor resistance to current therapies.-Franco, O. E., Tyson, D. R., Konvinse, K. C., Udyavar, A. R., Estrada, L., Quaranta, V., Crawford, S. E., Hayward, S. W. Altered TGF-α/β signaling drives cooperation between breast cancer cell populations.
authors.affiliation: Department of Surgery, NorthShore University HealthSystem, Evanston, Illinois, USA.
authors.forename: Omar E
authors.initials: OE
authors.lastname: Franco
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Tyson
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee, USA; and.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Konvinse
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Akshata R
authors.initials: AR
authors.lastname: Udyavar
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Estrada
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Vito
authors.initials: V
authors.lastname: Quaranta
authors.affiliation: Department of Surgery, NorthShore University HealthSystem, Evanston, Illinois, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Crawford
authors.affiliation: Department of Surgery, NorthShore University HealthSystem, Evanston, Illinois, USA; Department of Urologic Surgery, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee, USA; and Department of Cancer Biology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee, USA shayward@northshore.org.
authors.forename: Simon W
authors.initials: SW
authors.lastname: Hayward
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016513:Mice, SCID; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta
keywords: epithelial paracrine interactions; intratumor cooperation; tumor heterogeneity