Loss of PPARγ expression in mammary secretory epithelial cells creates a pro‐breast tumorigenic environment

Apostoli, Anthony J.; Skelhorne‐Gross, Graham; Rubino, Rachel; Peterson, Nichole; Lena, Michael A. Di; Schneider, M.; Sengupta, Sandip; Nicol, Christopher J.B.

doi:10.1002/ijc.28432

Cited by 38 publications

(38 citation statements)

References 42 publications

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“…Thus, we studied the mammary cancer risk in control and LP daughters using a well-established [5, 27] carcinogen-induced mouse model of breast cancer. Tumor latency was significantly shorter in LP daughters compared with controls ( P = 0.029; Fig.…”

Section: Resultsmentioning

confidence: 99%

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Paternal malnutrition programs breast cancer risk and tumor metabolism in offspring

et al. 2018

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BackgroundWhile many studies have shown that maternal factors in pregnancy affect the cancer risk for offspring, few studies have investigated the impact of paternal exposures on their progeny’s risk of this disease. Population studies generally show a U-shaped association between birthweight and breast cancer risk, with both high and low birthweight increasing the risk compared with average birthweight. Here, we investigated whether paternal malnutrition would modulate the birthweight and later breast cancer risk of daughters.MethodsMale mice were fed AIN93G-based diets containing either 17.7% (control) or 8.9% (low-protein (LP)) energy from protein from 3 to 10 weeks of age. Males on either group were mated to females raised on a control diet. Female offspring from control and LP fathers were treated with 7,12-dimethylbenz[a]anthracene (DMBA) to initiate mammary carcinogenesis. Mature sperm from fathers and mammary tissue and tumors from female offspring were used for epigenetic and other molecular analyses.ResultsWe found that paternal malnutrition reduces the birthweight of daughters and leads to epigenetic and metabolic reprogramming of their mammary tissue and tumors. Daughters of LP fathers have higher rates of mammary cancer, with tumors arising earlier and growing faster than in controls. The energy sensor, the AMP-activated protein kinase (AMPK) pathway, is suppressed in both mammary glands and tumors of LP daughters, with consequent activation of mammalian target of rapamycin (mTOR) signaling. Furthermore, LP mammary tumors show altered amino-acid metabolism with increased glutamine utilization. These changes are linked to alterations in noncoding RNAs regulating those pathways in mammary glands and tumors. Importantly, we detect alterations in some of the same microRNAs/target genes found in our animal model in breast tumors of women from populations where low birthweight is prevalent.ConclusionsOur study suggests that ancestral paternal malnutrition plays a role in programming offspring cancer risk and phenotype by likely providing a metabolic advantage to cancer cells.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1034-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

“…This established model of breast cancer has been used by us and others [5, 27]. Mice were examined for mammary tumors by palpation once per week, starting at week 2 after the last dose of DMBA and continue for a total of 20 weeks.…”

Section: Methodsmentioning

confidence: 99%

Paternal malnutrition programs breast cancer risk and tumor metabolism in offspring

et al. 2018

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“…This nuclear receptor acts as a tumor suppressor and the loss of its expression has been shown to contribute to the creation of a protumorigenic environment in breast tissue [34,35]. Therefore, the downregulation of this tumor suppressor could, together with impaired function of BRCA1, contribute to the increased susceptibility to breast cancer for carriers of specific BRCA1 missense mutations (p.Ala1708Glu, p.Gly1706Glu).…”

Section: Discussionmentioning

confidence: 96%

DNA repair capacity is impaired in healthy BRCA1 heterozygous mutation carriers

Vaclová

Gómez‐López

Setién

et al. 2015

Breast Cancer Res Treat

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BRCA1 germline mutations increase the lifetime risk of developing breast and ovarian cancers. However, taking into account the differences in disease manifestation among mutation carriers, it is probable that different BRCA1 mutations have distinct haploinsufficiency effects and lead to the formation of different phenotypes. Using lymphoblastoid cell lines derived from heterozygous BRCA1 mutation carriers and non-carriers, we investigated the haploinsufficiency effects of various mutation types using qPCR, immunofluorescence, and microarray technology. Lymphoblastoid cell lines carrying a truncating mutation showed significantly lower BRCA1 mRNA and protein levels and higher levels of gamma-H2AX than control cells or those harboring a missense mutation, indicating greater spontaneous DNA damage. Cells carrying either BRCA1 mutation type showed impaired RAD51 foci formation, suggesting defective repair in mutated cells. Moreover, compared to controls, cell lines carrying missense mutations displayed a more distinct expression profile than cells with truncating mutations, which is consistent with different mutations giving rise to distinct phenotypes. Alterations in the immune response pathway in cells harboring missense mutations point to possible mechanisms of breast cancer initiation in carriers of these mutations. Our findings offer insight into how various heterozygous mutations in BRCA1 could lead to impairment of BRCA1 function and provide strong evidence of haploinsufficiency in BRCA1 mutation carriers.

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“…Reversible white-to-pink transdifferentiation could shed light on breast cancer biology, as suggested by recent data showing that loss of PPARg expression by mammary secretory epithelial cells creates a pro-breast tumourigenic environment (69). Notably, PPARg seems to be a key factor for pink-to-white transdifferentiation in vitro (70).…”

Section: White-pink Plasticitymentioning

confidence: 97%

MECHANISMS IN ENDOCRINOLOGY: White, brown and pink adipocytes: the extraordinary plasticity of the adipose organ

Giordano

Smorlesi

Frontini

et al. 2014

European Journal of Endocrinology

224

177

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In mammals, adipocytes are lipid-laden cells making up the parenchyma of the multi-depot adipose organ. White adipocytes store lipids for release as free fatty acids during fasting periods; brown adipocytes burn glucose and lipids to maintain thermal homeostasis. A third type of adipocyte, the pink adipocyte, has recently been characterised in mouse subcutaneous fat depots during pregnancy and lactation. Pink adipocytes are mammary gland alveolar epithelial cells whose role is to produce and secrete milk. Emerging evidence suggests that they derive from the transdifferentiation of subcutaneous white adipocytes. The functional response of the adipose organ to a range of metabolic and environmental challenges highlights its extraordinary plasticity. Cold exposure induces an increase in the 'brown' component of the organ to meet the increased thermal demand; in states of positive energy balance, the 'white' component expands to store excess nutrients; finally, the 'pink' component develops in subcutaneous depots during pregnancy to ensure litter feeding. At the cell level, plasticity is provided not only by stem cell proliferation and differentiation but also, distinctively, by direct transdifferentiation of fully differentiated adipocytes by the stimuli that induce genetic expression reprogramming and through it a change in phenotype and, consequently function. A greater understanding of adipocyte transdifferentiation mechanisms would have the potential to shed light on their biology as well as inspire novel therapeutic strategies against metabolic syndrome (browning) and breast cancer (pinking).

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Loss of PPARγ expression in mammary secretory epithelial cells creates a pro‐breast tumorigenic environment

Cited by 38 publications

References 42 publications

Paternal malnutrition programs breast cancer risk and tumor metabolism in offspring

Paternal malnutrition programs breast cancer risk and tumor metabolism in offspring

DNA repair capacity is impaired in healthy BRCA1 heterozygous mutation carriers

MECHANISMS IN ENDOCRINOLOGY: White, brown and pink adipocytes: the extraordinary plasticity of the adipose organ

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