Abstract 3314: Normal breast tissue at risk for cancer development: A breast cancer initiating role for mammary adipocytes
Taekyu KangChristina YauStephen C. BenzGregor KringsRoman CamardaJ. E. HenryMark D. PowellChristopher C. Benz
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Adipocytes are the predominant cell population in the normal breast and while recent attention has pointed to adipocyte-tumor cell crosstalk as a driver of breast cancer biology there have been few reports on the potential role of adipocytes in driving breast cancer initiation. Because normal breast tissue studies have invariably used reduction mammoplasty, benign biopsy or cancer-adjacent tissues, we studied random breast core biopsy samples donated by 145 healthy, parous, non-obese, white women (median age = 45, range 27-66 y) without any history of breast cancer. Using questionnaire data to calculate future breast cancer risk (Gail scores), we compared digitized microscopic breast tissue (H&E) images with whole genome transcriptome profiling (RNAseq) from FFPE-extracted RNA. We used unsupervised hierarchical clustering of 1487 genes (normalized, median centered, log2-scaled RSEM values) to identify 32% of normal samples with an "Active" (vs. 68% "Inactive") transcriptome phenotype previously associated with later-life risk of death from breast cancer. Despite slightly lower BMI values, donors with the Active transcriptome phenotype showed significantly higher Gail scores as well as higher mammary adipocyte nuclei counts (median 80% vs. 60%, p=2.3e-6). Tissue resident leukocytes were uncommon but Active transcriptome tissues expressed significantly altered immune modules enriched in TGFβ, interferon and macrophage gene signatures (including single gene increase in CD68) and depleted (relative to Inactive samples) of CD8+ T-cell and serum response/inflammation/wound healing signatures. Active samples were not enriched in cell senescence, SASP or DNA damage response gene signatures but were enriched in an autophagy-to-senescence-transition (AST) signature with increased CAV1 (caveolin-1, p=2.7e-12) and BNIP3 (Bcl2 interacting protein-3, p=4.7e-05) expression, genes that also regulate lipoprotein digestion/mobilization and adipocyte remodeling. Strongest among significant associations linking Active with adipocyte-enriched normal breast samples were increases in two adipokine growth factors, IGF-1 (p=2.2e-16) and FGF2 (p=3.0e-11), the adipokine (resistin) receptor CAP1 (p=0.04) recently linked to poor breast cancer outcomes, and a cAMP-dependent pro-lipolytic signature (p=0.01) known to drive breast cancer progression which, in these samples, correlated positively with average adipocyte area values. Altogether, the collective histologic and molecular features characterizing the normal breast tissue of >30% of healthy parous and non-obese women with increased predicted breast cancer risk seem to implicate a dysregulated mammary adipocyte microenvironment similar to but distinct from that associated with established breast tumors, that precedes microscopic and clinical evidence of breast tumorigenesis.Citation Format: Taekyu Kang, Christina Yau, Stephen Benz, Gregor Krings, Roman Camarda, Jill E. Henry, Mark Powell, Christopher C. Benz. Normal breast tissue at risk for cancer development: A breast cancer initiating role for mammary adipocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3314.Keywords:
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Laboratoire de Physiologie de la Lactation, Institut National de la Recherche Agronomique, 78350-Jouy-en-Josas, France (Received 23 December 1974) Hormonal induction of milk synthesis by the ruminant mammary gland in organ culture has received little attention. M. A. Cannata, C. Delouis, C. Jeulin & R. Denamur (unpublished observation) demonstrated the lactogenic effect of insulin + cortisol + prolactin in vitro on ewe mammary tissue with lobulo-alveolar development at the time of explantation, but there are no data on the induction of milk secretion in bovine mammary tissue cultured on a synthetic medium. Therefore, we have studied the culture conditions necessary to maintain bovine mammary tissue and the combination of hormones needed to induce milk secretion. Biopsy samples were obtained from 2-year-old French Friesian heifers at various times during the oestrous cycle, after i.m. injection of the tranquillizer, xylazine (Rompun, Bayer; 2% solution, 1·5 ml/100 kg body weight). Expiants (1 mm3) were
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The uptake and clearance of chemical carcinogens by mammary tissue are for the most part obscured by the large amount of fat surrounding the mammary parenchymal tissue. This is due primarily to the lipophilic nature of the carcinogenic polycyclic hydrocarbons. Therefore, it became necessary to develop a procedure whereby mammary gland adipose tissue cells may be separated from mammary parenchymal tissue without removal of intracellular lipid or the disruption of the tissue beyond histologic recognition. The procedure developed involves the incubation of the tissue with the enzyme collagenase in a tissue culture medium for 1-1 ½ hr. This is followed by several sodium chloride washes which effectively remove any adhering intact fat cells. Lipid content of the collagenasetreated preparation was decreased from approximately 60% to 2% when compared with the untreated control gland. The procedure described effectively separates intact fat cells from mammary parenchymal tissue but maintains a histologic state in which mammary ducts and alveoli may be readily identified.
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