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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.01279

Fry is required for mammary gland development during pregnant periods and affects the morphology and growth of breast cancer cells

 Yan Liu1, 2,  Xushen Chen1,  Zhihong Gong1, 3, Hao Zhang1, Fan Fei4, Xiaojiang Tang4, Jie Wang5, Peilin Xu2,  Helmut Zarbl6 and Xuefeng Ren1*
  • 1University at Buffalo, United States
  • 2Sun Yat-sen University, China
  • 3Roswell Park Comprehensive Cancer Center, University at Buffalo, United States
  • 4Guangdong Medical Laboratory Animal Center (GDMLAC), China
  • 5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, University at Buffalo, United States
  • 6Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, United States

The Fry gene, located on chromosome 13, is an evolutionarily conserved large protein from yeast to human. Our previous study genetically linked the Fry gene with differential susceptibility to mammary carcinogenesis, but whether Fry affects mammary gland development and function, as well as the growth of breast cancer cells, is largely unknown. To define the consequences of Fry loss in the mammary glands, we have generated mice conditionally deficient of the Fry gene in the mammary glands using the Cre-loxP recombination system. We examined multiple phenotypes with male and female homozygous Fry conditional knockout mice (Mfry) and control mice (WT), including body weight, preliminary observations (health and neurological flexes), open field locomotion, sensory abilities, auditory threshold, and glucose metabolism. The loss of Fry in the mammary glands didn’t cause a significant difference in these genotypes between Mfry and WT mice. However, our data showed that Fry was required during pregnancy, while it was functionally dispensable in virgin mammary gland development. Loss of Fry led to more lateral buds, and the lobuloalveoli were smaller and showed undistended morphology in mammary glands during late pregnancy. In vitro experiment, ectopic expression of FRY could alter the morphology and significantly suppress the growth and proliferation of the breast cancer cell lines, MDA-MB-231 (ER-/PR-/HER2-, Basal-like) and BT474 (ER+/PR+/HER2+, Luminal B). The following genome-wide transcriptomic analysis of these cells suggested that FRY inter-acted with protein kinases relevant signaling pathways and induced massive changes in gene expression, including the activation of the Hippo/Yap pathway. Together, our data suggest that the FRY is required for mammary glands developments during pregnant periods, and affects breast cancer cell growth and proliferation.

Keywords: Fry gene, Conditional knock out mice, mammary gland development, Hippo/YAP signaling pathway, Cancer cell growth

Received: 03 Sep 2019; Accepted: 04 Nov 2019.

Copyright: © 2019 Liu, Chen, Gong, Zhang, Fei, Tang, Wang, Xu, Zarbl and Ren. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Xuefeng Ren, University at Buffalo, Buffalo, United States, xuefengr@buffalo.edu