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
| Autor: | Gail E. Tomlinson, Abhik Bandyopadhyay, Shu Lin, I-Tien Yeh, Abdel G. Elkahloun, Lu-Zhe Sun, John E. Cornell, Junhua Yang, Joseph K. Agyin, Long Wang |
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| Rok vydání: | 2012 |
| Předmět: |
Mice
Nude Breast Neoplasms Oncogene Protein p21(ras) Cell Line 03 medical and health sciences Mice 0302 clinical medicine Transforming Growth Factor beta Animals Humans RNA Small Interfering Autocrine signalling Mammary Glands Human Molecular Biology Cellular Senescence 030304 developmental biology 0303 health sciences Gene knockdown biology Microarray analysis techniques Epithelial Cells Cell Biology Transforming growth factor beta Articles Signaling body regions ErbB Receptors Cell Transformation Neoplastic Receptors Estrogen 030220 oncology & carcinogenesis biology.protein Cancer research ras Proteins Female RNA Interference Signal transduction Receptors Progesterone Cell aging Transforming growth factor Signal Transduction |
| Zdroj: | Molecular Biology of the Cell |
| ISSN: | 1939-4586 |
| Popis: | A series of isogenic, basal-like human mammary epithelial cells (HMECs) with altered TGF-β sensitivity and different malignancy is used to elucidate molecular mechanisms that evade oncogenic Ras-induced growth arrest and promote transformation. Attenuation of TGF-β signaling is found to cause metastatic progression of Ras-transformed HMECs. 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. |
| Databáze: | OpenAIRE |
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