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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