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.
Background: While genetics explains some familial breast cancer cases, we showed that environmentally-induced epigenetic inheritance of breast cancer can also occur in rodent models. We previously reported that paternal consumption of a high-fat diet and ensuing obesity increased breast cancer susceptibility in the offspring (F1). Nevertheless, it is still unclear whether paternal-induced programming of breast cancer in daughters is associated with systemic alterations or mammary epithelium-specific factors. It also remains to be determined whether the ancestrally programmed breast cancer predisposition in F1 progeny can be transmitted to subsequent generations. Methods: Male mice (F0) were fed either a control (CO) diet or an obesity-inducing diet (OID) for seven weeks and then mated with female mice (F0) reared on a CO diet. The resulting offspring (F1), also exclusively fed CO diet, were either used for mammary gland and tumor transplantation surgeries or to generate the F2 generation. To induce the mammary tumors, female mice were treated with 7,12 dimethylbenz[a]anthracene (DMBA). Total RNA extracted from F0 or F1 males sperm was used for small RNA-Seq analysis. Results: Mammary glands from F1 CO female offspring exhibited enhanced development when transplanted into OID females [OID(CO-MG)], as shown by higher mammary gland area, epithelial branching and elongation, compared to CO females that received a CO mammary gland [CO(CO-MG)]. Similarly, mammary tumors from F1 CO female offspring transplanted into OID females [OID(CO.T)] displayed improved growth with a higher proliferation/apoptosis rate. We also found that granddaughters (F2) from the OID grand-paternal germline showed accelerated tumor growth compared to COxCO granddaughters (F2). Transmission of breast cancer predisposition to the F2 generation through OID male germline was associated with alterations in specific sperm tRNA fragments (tRF) in both F0 and F1 males.Conclusions: Our findings indicate that systemic metabolic and mammary stromal alterations are the most significant contributors to paternal programming of mammary gland development and cancer predisposition in female offspring rather than mammary epithelium confined factors. Our data also show breast cancer predisposition in OID daughters can be transmitted to subsequent generations and could explain some familial cancers, if confirmed in humans.
21Background: While genetics explains some familial breast cancer cases, we showed that 22 environmentally-induced epigenetic inheritance of breast cancer can also occur in rodent 23 models. We previously reported that paternal consumption of a high-fat diet and ensuing obesity 24 increased breast cancer susceptibility in the offspring (F1). Nevertheless, it is still unclear 25 whether paternal-induced programming of breast cancer in daughters is associated with systemic 26 alterations or mammary epithelium-specific factors. It also remains to be determined whether 27 the ancestrally programmed breast cancer predisposition in F1 progeny can be transmitted to 28 subsequent generations. 29Methods: Male mice (F0) were fed either a control (CO) diet or an obesity-inducing diet (OID) 30 for seven weeks and then mated with female mice (F0) reared on a CO diet. The resulting 31 offspring (F1), also exclusively fed CO diet, were either used for mammary gland and tumor 32 transplantation surgeries or to generate the F2 generation. To induce the mammary tumors, 33 female mice were treated with 7,12 dimethylbenz[a]anthracene (DMBA). Total RNA extracted 34 from F0 or F1 males sperm was used for small RNA-Seq analysis. 35Results: Mammary glands from F1 CO female offspring exhibited enhanced development when 36 transplanted into OID females [OID(CO-MG)], as shown by higher mammary gland area, 37 epithelial branching and elongation, compared to CO females that received a CO mammary 38 gland [CO(CO-MG)]. Similarly, mammary tumors from F1 CO female offspring transplanted 39 into OID females [OID(CO.T)] displayed improved growth with a higher proliferation/apoptosis 40 rate. We also found that granddaughters (F2) from the OID grand-paternal germline showed 41 accelerated tumor growth compared to COxCO granddaughters (F2). Transmission of breast 42 cancer predisposition to the F2 generation through OID male germline was associated with 43 alterations in specific sperm tRNA fragments (tRF) in both F0 and F1 males. 44 Conclusions:Our findings indicate that systemic metabolic and mammary stromal alterations 45 are the most significant contributors to paternal programming of mammary gland development 46 and cancer predisposition in female offspring rather than mammary epithelium confined factors. 47Our data also show breast cancer predisposition in OID daughters can be transmitted to 48 subsequent generations and could explain some familial cancers, if confirmed in humans. 49 50 Insulin tolerance test (ITT) was performed after the mice fasted for 6 h, according to the method 113 described by Takada et al [21]. The insulin load (75 mU/100 g body weight) was injected as a 114 bolus, and the blood glucose levels were determined at 0, 3, 6, 9, 12, and 30 minutes after 115 injection in female offspring. The area under the curve (AUC) was calculated according to the 116 trapezoid rule. Differences in ITT were analyzed using two-way ANOVA (group, time), 117 followed by post-hoc analyses.
Introduction: Mastocytosis, a clonal proliferation of mast cells commonly involving the skin and bone marrow, has a varied clinical presentation ranging from cutaneous lesions to systemic disease. Cutaneous mastocytosis is managed symptomatically, but systemic mastocytosis is treated with targeted therapy against the mutated receptor tyrosine kinase c-KIT, the pathogenic driver of mastocytosis. However, there are no guidelines for the treatment of cutaneous mastocytosis refractory to symptomatic management. We herein report a method to select genetically informed therapy for symptomatic and recalcitrant cutaneous mastocytosis. Case presentation: We performed a mutational analysis of dermal mast cells after enrichment by laser capture in a 23-year-old woman with recalcitrant cutaneous mastocytosis. The analysis revealed a aspartic acid to valine substitution at codon 816 (D816V) mutation in the protein c-KIT. Based on these results, we initiated treatment with the multi-kinase/KIT inhibitor midostaurin, a treatment effective against the D816V c-KIT mutation. After 3 months of treatment, the patient exhibited a reduction in the number and size of cutaneous lesions and reported resolution of pruritus and decreased severity of other mast cell-related symptoms. Discussion: The treatment of mastocytosis relies heavily on whether the disease is limited to the skin or systemic. However, there are no guidelines for cutaneous mastocytosis that does not respond to symptomatic management. In the present report describing a patient with recalcitrant cutaneous mastocytosis, we describe a strategy in which skin mutational analysis is used to guide the selection of targeted therapy. Conclusion: Performing mast cell mutational analyses in the skin provides a means to select targeted therapy for symptomatic and refractory cutaneous mastocytosis.
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