Abstract
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 interacted 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.
Highlights
The furry (Fry) gene was originally identified in 2001 as a Drosophila gene involved in maintaining the integrity of cellular extensions during morphogenesis [1]
Fry was identified in our previous genetic linkage studies using inbred rat models of heritable mammary cancer to identify susceptibility genes and was associated with the resistance of the COP rat strain to N’-Methyl-N’-Nitrosourea (NMU) -induced mammary carcinogenesis [18]
We identified a novel role for Fry in regulating mammary gland development
Summary
The furry (Fry) gene was originally identified in 2001 as a Drosophila gene involved in maintaining the integrity of cellular extensions during morphogenesis [1]. It has 5–6 conserved regions, including FRY N-terminal domain (FND) consisting of HEAT/Armadillo-like repeats. Some studies have suggested a role of FRY in cancer development. We examined multiple phenotypes between Mfry and control mice, focusing on the role of Fry in mammary gland development in different life stages. Our in vitro studies show that FRY affects morphology and suppresses the growth and proliferation of breast cancer cells, which is likely related to its interaction with protein kinases and associated signaling pathways
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