Integrin Alpha V Beta 3 Expression in Luminal Breast Cancer Cells Promotes their Reversion to Acinar-Like Structure in Conjunction with their Relevant Microenvironment

Hanan Abu-Tayeh ¹ Keren Weidenfeld ¹ Alisa Zhilin-Roth ¹ Sagie Schif-Zuck ¹ Sonja Thaler ² Cristina Cotarelo ³ Tuan Zea Tan ⁴ Jean Paul Thiery ⁵ Geula Klorin ⁷ Jeffrey Green ⁶ Edmond Sabo ⁷ Jonathan P. Sleeman ⁸ Maty Tzukerman ⁹ Dalit Barkan ¹

¹Department of Human Biology, University of Haifa
²Campus Nord, Institut für Toxikologie und Genetik, Karlsruhe Institute of Technology (KIT)
³Department of Pathology, University Medical Center Mainz, Langenbeckstr
⁴National University of Singapore, Cancer Science Institute of Singapore
⁵A*STAR, Institute of Molecular and Cell Biology
⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute
⁷Department of Pathology, Rambam Medical Center
⁸Medical Faculty Mannheim, Centre for Biomedicine and Medical Technology Mannheim (CBTM), University of Heidelberg
⁹Molecular Medicine Laboratory, Rapport Faculty of Medicine, Technion-Israel Institute of Technology

Re-establishing tissue organization of breast cancer cells into acini was shown previously to override their malignant phenotype. Here we demonstrate that expression of Integrin αvβ3 (Int- αvβ3) in luminal A breast cancer cell lines reverts them back to a normal-like acini when cultured in their relevant 3-D microenvironment. These acini like structures expressed the milk protein beta casein thus resembling normal alveolar cells. Importantly, this reversion promoted their growth arrest and was mediated by Int-αvβ3 expression and activation on cancer luminal progenitor-like cells (CLPC). Furthermore, downregulation of NOTCH-4 expression and downstream signaling was shown to mediate this reversion. Intriguingly, by utilizing a humanized tumor microenvironment model based on the potential of human embryonic stem cells to generate teratomas in immunodeficient mice, we could demonstrate that Int-αvβ3 expression in luminal A breast cancer cells promoted their differentiation when placed in mature teratomas. Furthermore, Int-αvβ3 expression was mostly detected in benign stage of human breast tissues.

Hence, this data proposes a novel strategy to ‘normalize’ the malignant phenotype by reprogramming CLPC to differentiate via the expression of Int-αVβ3. Therefore, promoting such differentiation of luminal breast cancer cells in conjunction with their microenvironment may serve as a novel approach to combat local recurrences of breast cancers that resist conventional therapies, thus keeping them on halt.