Altered Expression of TGF-beta Facilitates Breast Cancer Cell Growth, Division, Migration, and Metastasis

Shannon Ranney

Introduction: Breast cancer is one of the most common cancers in females worldwide, with metastasis being the most common cause of death among patients with breast cancer1. There are nearly 1.7 million new cases diagnosed every year, and 1 in 8 women in the U.S. developing breast cancer in their lifetime2. Transforming growth factor-β (TGF-β) is a major participant in the pathogenesis of breast cancer, initially serving as a tumor suppressor and later a tumor promotor. This is known as the TGF-β paradox3. However, tumor cells are able to evade TGF-β induced apoptosis by down regulating certain aspects of the TGF-β signaling pathway, or by certain mutations of Smad proteins implicated in tumorigenesis4. Specifically, TGF-β can induce epithelial-mesenchymal-transition (EMT) via activation of multiple Smad-dependent pathways5. As a result of its tumor promoting capabilities, TGF-β and its downstream signaling pathway serve as potential for specific breast cancer therapies. One such therapy being researched is heme-oxygenase-1 (HMOX-1), a microsomal enzyme with the potential to limit migration and invasion of cancers5. Methods: MCF-7 human breast cancer cell lines were transfected with HMOX-1 siRNA5. Subsequently, PCR, western blot, migration and invasion assays, immunofluorescence assays, and fluorescent ROS assays were performed, analyzed, and compared5. Results: Usually, TGF-β causes the release of ROS and then induces EMT by activating E-cadherin repressors via Smad2/3, or Smad-independent pathways such as PI3K, MAPK, and Rho family GTPase pathways5. However, this study showed that hemin induces HMOX-1 expression in the breast cancer cell lines, and thus inhibits migration, invasion, and EMT5. Increased HMOX-1 expression via hemin stimulation inhibits TGF-β induced EMT by regulated the release of ROS and the dependent pathways5. This inhibition was significantly attenuated by the transfection of HMOX-1 siRNA into hemin-treated MCF-7 breast cancer cells5. It was also found that HMOX-1 enhanced the expression of E-cadherin, an intracellular adhesion molecule that plays a role in tumor suppression5. Conclusions: This study found that HMOX-1 has the capacity to suppress the invasiveness of breast cancer by reducing TGF-β initiated EMT5. HMOX-1 expression is increased via hemin stimulation in the cell lines, and subsequently TGF-β induced EMT is inhibited and metastatic capabilities diminished5. Breast cancer remains a problem for women across the globe. Further research into TGF-b and its downstream pathways should be pursued to discover more potential breast cancer therapies, such as HMOX-1.

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  2. Winters S, Martin C, Murphy D, Shokar N. Breast Cancer Epidemiology, Prevention, and Screening. Progress in Molecular Biology and Translational Science. 2017;151:1-32. https://www-sciencedirect-com.ezproxy.library.tamu.edu/science/article/pii/S1877117317301126?via%3Dihub. Acessed February 25, 2019.
  3. Ibrahim Y, Hachim M, Mahmood Y, et al. A dual prognostic role for the TGF receptors in human breast cancer. Human Pathology (2016) 57, 140-151. https://www-sciencedirect-com.srv-proxy2.library.tamu.edu/science/article/pii/S0046817716301435?via%3Dihub
  4. Haque S and Morris JC. Transforming growth factor-b: A therapeutic target for cancer. Human Vaccines & Immunotherapeutics. 2017; 13(8):1741-1750. https://www-ncbi-nlm-nih-gov.srv-proxy2.library.tamu.edu/pmc/articles/PMC5557219/pdf/khvi-13-08-1327107.pdf. April 3, 2019.
  5. Zhu X, Huang S, Zeng L, et al. HMOX-1 inhibits TGF-β-induced epithelial- mesenchymal transition in the MCF-7 breast cancer cell line. International Journal of Molecular Medicine (2017) 40: 411-417. https://www-ncbi-nlm-nih-gov.srv- proxy2.library.tamu.edu/pmc/articles/PMC5505025/pdf/ijmm-40-02-0411.pdf. April 2, 2019.