title: Attenuation of TGF-β signaling suppresses premature senescence in a p21-dependent manner and promotes oncogenic Ras-mediated metastatic transformation in human mammary epithelial cells.
abstract: The molecular mechanisms that drive triple-negative, basal-like breast cancer progression are elusive. Few molecular targets have been identified for the prevention or treatment of this disease. Here we developed a series of isogenic basal-like human mammary epithelial cells (HMECs) with altered transforming growth factor-β (TGF-β) sensitivity and different malignancy, resembling a full spectrum of basal-like breast carcinogenesis, and determined the molecular mechanisms that contribute to oncogene-induced transformation of basal-like HMECs when TGF-β signaling is attenuated. We found that expression of a dominant-negative type II receptor (DNRII) of TGF-β abrogated autocrine TGF-β signaling in telomerase-immortalized HMECs and suppressed H-Ras-V12-induced senescence-like growth arrest (SLGA). Furthermore, coexpression of DNRII and H-Ras-V12 rendered HMECs highly tumorigenic and metastatic in vivo in comparison with H-Ras-V12-transformed HMECs that spontaneously escaped H-Ras-V12-induced SLGA. Microarray analysis revealed that p21 was the major player mediating Ras-induced SLGA, and attenuated or loss of p21 expression contributed to the escape from SLGA when autocrine TGF-β signaling was blocked in HMECs. Furthermore, knockdown of p21 also suppressed H-Ras-V12-induced SLGA. Our results identify that autocrine TGF-β signaling is an integral part of the cellular anti-transformation network by suppressing the expression of a host of genes, including p21-regulated genes, that mediate oncogene-induced transformation in basal-like breast cancer.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Lin
authors.forename: Junhua
authors.initials: J
authors.lastname: Yang
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.forename: Abhik
authors.initials: A
authors.lastname: Bandyopadhyay
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.forename: John E
authors.initials: JE
authors.lastname: Cornell
authors.forename: I-Tien
authors.initials: IT
authors.lastname: Yeh
authors.forename: Joseph
authors.initials: J
authors.lastname: Agyin
authors.forename: Gail
authors.initials: G
authors.lastname: Tomlinson
authors.forename: Lu-Zhe
authors.initials: LZ
authors.lastname: Sun
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D066246:ErbB Receptors / Q000172:deficiency; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen / Q000172:deficiency; D011980:Receptors, Progesterone / Q000172:deficiency; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016212:Transforming Growth Factor beta; D066246:ErbB Receptors; D015689:Oncogene Protein p21(ras); D018631:ras Proteins