Abstract
We previously showed that environmentally-induced epigenetic inheritance of cancer occurs in rodent models. For instance, we reported that paternal consumption of an obesity-inducing diet (OID) increased breast cancer susceptibility in the offspring (F1). Nevertheless, it is still unclear whether programming of breast cancer in daughters is due to systemic alterations or mammary epithelium-specific factors and whether the breast cancer predisposition in F1 progeny can be transmitted to subsequent generations. In this study, we show that mammary glands from F1 control (CO) female offspring exhibit enhanced growth when transplanted into OID females compared to CO mammary glands transplanted into CO females. Similarly, carcinogen-induced mammary tumors from F1 CO female offspring transplanted into OID females has a higher proliferation/apoptosis rate. Further, we show that granddaughters (F2) from the OID grand-paternal germline have accelerated tumor growth compared to CO granddaughters. This between-generation transmission of cancer predisposition is associated with changes in sperm tRNA fragments in OID males. Our findings indicate that systemic and mammary stromal alterations are significant contributors to programming of mammary development and likely cancer predisposition in OID daughters. Our data also show that breast cancer predisposition is transmitted to subsequent generations and may explain some familial cancers, if confirmed in humans.
Highlights
We previously showed that environmentally-induced epigenetic inheritance of cancer occurs in rodent models
SCLB Somatic cell lysis buffer terminal end buds (TEB) Terminal end buds t-RNA fragments (tRFs) tRNA-derived fragments obesity-inducing diet (OID) daughters/females Daughters of OID fed males CO daughters/females Daughters of CO diet fed males [CO(CO-MG)] Mammary gland from F1 CO female offspring transplanted into CO female offspring [CO(OID-MG)] Mammary gland from F1 OID female offspring transplanted into CO female offspring [OID(CO-MG)] Mammary tumor from F1 CO female offspring transplanted into OID female offspring [CO(OID.T)] Mammary tumor from F1 OID female offspring transplanted into CO female offspring [CO(CO.T)] Mammary tumor from F1 CO female offspring transplanted into CO female offspring. [OID(CO.T)] Mammary tumor from F1 CO female offspring transplanted into OID female offspring
Mammary glands of OID daughters showed increased number of terminal end buds (TEB), higher epithelial branching and elongation, only the last parameter reached statistical significance compared to CO (Table S1)
Summary
We previously showed that environmentally-induced epigenetic inheritance of cancer occurs in rodent models. We reported that paternal consumption of an obesity-inducing diet (OID) increased breast cancer susceptibility in the offspring (F1) It is still unclear whether programming of breast cancer in daughters is due to systemic alterations or mammary epitheliumspecific factors and whether the breast cancer predisposition in F1 progeny can be transmitted to subsequent generations. Published studies demonstrated that the small RNA load in paternal sperm can convey phenotypes to the progeny[3,7,8,9] Some of those reports implicate t-RNA fragments (tRFs)—which are the most abundant small RNA sub-type in sperm—in the transmission of environmentally-induced information from fathers to offspring and show that they can recapitulate disease phenotypes[7,8,9,10]
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