Transcriptome analysis of the hormone-sensing cells in mammary epithelial reveals dynamic changes in early pregnancy

BMC Developmental Biology

Alexandra M Pietersen²  Sujoy Ghosh¹  Kamini Kunasegaran³  Duvini De Silva³ 

[1] Program in Cardiovascular & Metabolic Disorders, Duke-NUS Graduate Medical School, 8 College Rd, Singapore 169857, Singapore;Department of Physiology, National University of Singapore, 21 Lower Kent Ridge Rd, Singapore 119077, Singapore;Program in Cancer & Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College, Rd, Singapore, 169857, Singapore

关键词: Microarray;    Estrogen receptor;    Proliferation;    Single cell analysis;    Morphogenesis;    Mammary gland;   

Others  :  1118593
DOI  :  10.1186/s12861-015-0058-9

 received in 2014-08-30, accepted in 2015-01-15,  发布年份 2015

【 摘 要 】

Background

Alveoli, the milk-producing units of the mammary gland, are generated during pregnancy by collaboration of different epithelial cell types. We present the first analysis of transcriptional changes within the hormone sensing population during pregnancy. Hormone-receptor positive (HR+) cells play a key role in the initiation of alveologenesis as they sense systemic hormonal changes and translate these into local instructions for neighboring HR- cells. We recently showed that IGF2 is produced specifically by HR+ cells in early pregnancy, but is undetectable in the virgin state. Here, we define the transcriptome of HR+ cells in early pregnancy with the aim to elucidate additional changes that are unique for this dynamic developmental time window.

Results

We harvested mammary glands from virgin, 3-day and 7-day pregnant mice and isolated a few hundred hormone-sensing cells per animal by FACS for microarray analysis. There was a high concordance between animals with a clear induction of cell cycle progression genes at day 3 of pregnancy and molecules involved in paracrine signalling at day 7.

Conclusions

These findings underscore the proliferative capacity of HR+ cells upon specific stimuli and elucidate developmentally-restricted changes in cellular communication. Since the majority of breast cancers are HR+, with a variable proportion of HR+ cells per tumor, we anticipate that this data set will aid further studies into the regulation of HR+ cell proliferation and the role of heterotypic signalling within tumors.

【 授权许可】

   
2015 De Silva et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Brisken C, O’Malley B: Hormone action in the mammary gland. Cold Spring Harbor Perspectives in Biology 2010, 2:a003178.
• [2]Tarulli GA, De Silva D, Ho V, Kunasegaran K, Ghosh K, Tan BC, et al.: Hormone-sensing cells require Wip1 for paracrine stimulation in normal and premalignant mammary epithelium. Breast Cancer Res 2013, 15:R10. BioMed Central Full Text
• [3]Kendrick H, Regan JL, Magnay F-A, Grigoriadis A, Mitsopoulos C, Zvelebil M, et al.: Transcriptome analysis of mammary epithelial subpopulations identifies novel determinants of lineage commitment and cell fate. BMC Genomics 2008, 9:591. BioMed Central Full Text
• [4]Clarke RB, Howell A, Potten CS, Anderson E: Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res 1997, 57:4987-91.
• [5]Zeps N, Bentel JM, Papadimitriou JM, D’Antuono MF, Dawkins HJ: Estrogen receptor-negative epithelial cells in mouse mammary gland development and growth. Differentiation 1998, 62:221-6.
• [6]Shehata M, Teschendorff A, Sharp G, Novcic N, Russell A, Avril S, et al.: Phenotypic and functional characterization of the luminal cell hierarchy of the mammary gland. Breast Cancer Res 2012, 14:R134. BioMed Central Full Text
• [7]Wicha MS: Targeting breast cancer stem cells. Breast 2009, 18:S56-8.
• [8]Lim E, Wu D, Pal B, Bouras T, Asselin-Labat M-L, Vaillant F, et al.: Transcriptome analyses of mouse and human mammary cell subpopulations reveal multiple conserved genes and pathways. Breast Cancer Res 2010, 12:R21. BioMed Central Full Text
• [9]Ewan KBR, Oketch-Rabah HA, Ravani SA, Shyamala G, Moses HL, Barcellos-Hoff MH: Proliferation of estrogen receptor-alpha-positive mammary epithelial cells is restrained by transforming growth factor-beta1 in adult mice. Am J Pathol 2005, 167:409-17.
• [10]Mastroianni M, Kim S, Kim YC, Esch A, Wagner C, Alexander CM: Wnt signaling can substitute for estrogen to induce division of ERα-positive cells in a mouse mammary tumor model. Cancer Lett 2010, 289:23-31.
• [11]Beleut M, Rajaram RD, Caikovski M, Ayyanan A, Germano D, Choi Y, et al.: Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland. Proc Natl Acad Sci 2010, 107:2989-94.
• [12]van Amerongen R, Bowman AN, Nusse R: Developmental stage and time dictate the fate of Wnt/β-catenin-responsive stem cells in the mammary gland. Cell Stem Cell 2012, 11:387-400.
• [13]Šale S, Lafkas D, Artavanis-Tsakonas S: Notch2 genetic fate mapping reveals two previously unrecognized mammary epithelial lineages. Nat Cell Biol 2013, 15:1-11.
• [14]Chang TH-T, Kunasegaran K, Tarulli GA, De Silva D, Voorhoeve PM, Pietersen AM: New insights into lineage restriction of mammary gland epithelium using parity-identified mammary epithelial cells. Breast Cancer Res 2014, 16:R1. BioMed Central Full Text
• [15]Alexander CM, Joshi PA, Khokha R: Fully Interlocking: A Story of Teamwork among Breast Epithelial Cells. Dev Cell 2014, 28:114-5.
• [16]Lee HJ, Ormandy CJ: Interplay between progesterone and prolactin in mammary development and implications for breast cancer. Mol Cell Endocrinol 2012, 357:101-7.
• [17]Brisken C, Kaur S, Chavarria T, Binart N: Prolactin controls mammary gland development via direct and indirect mechanisms. Dev Biol 1999, 210:96-106.
• [18]Lange CA, Shen T, Horwitz KB: Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26S proteasome. Proc Natl Acad Sci U S A 2000, 97:1032-7.
• [19]Hilton HN, Doan TB, Graham JD, Oakes SR, Silvestri A, Santucci N, et al.: Acquired convergence of hormone signaling in breast cancer: ER and PR transition from functionally distinct in normal breast to predictors of metastatic disease. Oncotarget 2014, 5:8651-64.
• [20]Ho V, Yeo SY, Kunasegaran K, De Silva D, Tarulli GA, Voorhoeve PM, et al.: Expression analysis of rare cellular subsets: direct RT-PCR on limited cell numbers obtained by FACS or soft agar assays. BioTechniques 2013, 54:208-12.
• [21]Domené HM, Scaglia PA, Jasper HG: Deficiency of the insulin-like growth factor-binding protein acid-labile subunit (ALS) of the circulating ternary complex in children with short stature. Pediatr Endocrinol Rev 2010, 7:339-46.
• [22]Tonner E, Barber MC, Allan GJ, Beattie J, Webster J, Whitelaw CBA, et al.: Insulin-like growth factor binding protein-5 (IGFBP-5) induces premature cell death in the mammary glands of transgenic mice. Development 2002, 129:4547-57.
• [23]Chatterjee S, Bacopulos S, Yang W, Amemiya Y, Spyropoulos D, Raouf A, et al.: Loss of igfbp7 causes precocious involution in lactating mouse mammary gland. PLoS One 2014, 9:e87858.
• [24]Kaffer CR, Grinberg A, Pfeifer K: Regulatory mechanisms at the mouse Igf2/H19 locus. Mol Cell Biol 2001, 21:8189-96.
• [25]Gaudet S, Branton D, Lue RA: Characterization of PDZ-binding kinase, a mitotic kinase. Proc Natl Acad Sci U S A 2000, 97:5167-72.
• [26]Lei M, Tye BK: Initiating DNA synthesis: from recruiting to activating the MCM complex. J Cell Sci 2001, 114:1447-54.
• [27]Miyagawa K, Tsuruga T, Kinomura A, Usui K, Katsura M, Tashiro S, et al.: A role for RAD54B in homologous recombination in human cells. EMBO J 2002, 21:175-80.
• [28]Ismail PM, DeMayo FJ, Amato P, Lydon JP: Progesterone induction of calcitonin expression in the murine mammary gland. J Endocrinol 2004, 180:287-95.
• [29]Lu SS, Becker KAK, Hagen MJM, Yan HH, Roberts ALA, Mathews LAL, et al.: Transcriptional responses to estrogen and progesterone in mammary gland identify networks regulating p53 activity. Endocrinology 2008, 149:4809-20.
• [30]Levina V, Su Y, Gorelik E: Immunological and nonimmunological effects of indoleamine 2,3-dioxygenase on breast tumor growth and spontaneous metastasis formation. Clin Dev Immunol 2012, 2012:173029.
• [31]Soliman H, Rawal B, Fulp J, Lee J-H, Lopez A, Bui MM, et al.: Analysis of indoleamine 2-3 dioxygenase (IDO1) expression in breast cancer tissue by immunohistochemistry. Cancer Immunol Immunother 2013, 62:829-37.
• [32]Yu X, Shen H, Liu L, Lin L, Gao M, Wang S: Changes of sodium iodide symporter regulated by IGF-I and TGF-β1 in mammary gland cells from lactating mice at different iodine levels. Biol Trace Elem Res 2012, 146:73-8.
• [33]Said TK, Conneely OM, Medina D, O’Malley BW, Lydon JP: Progesterone, in addition to estrogen, induces cyclin D1 expression in the murine mammary epithelial cell, in vivo. Endocrinology 1997, 138:3933-9.
• [34]Lain AR, Creighton CJ, Conneely OM: Research resource: progesterone receptor targetome underlying mammary gland branching morphogenesis. Mol Endocrinol 2013, 27:1743-61.
• [35]Hurle B, Swanson W, Swanson W, Green ED: Comparative sequence analyses reveal rapid and divergent evolutionary changes of the WFDC locus in the primate lineage. Genome Res 2007, 17:276-86.
• [36]Amiano NO, Costa MJ, Reiteri RM, Payés C, Guerrieri D, Tateosian NL, et al.: Anti-tumor effect of SLPI on mammary but not colon tumor growth. J Cell Physiol 2013, 228:469-75.
• [37]Crouch EC: Structure, biologic properties, and expression of surfactant protein D (SP-D). Biochim Biophys Acta (BBA) - Mol Basis Dis 1997, 1408:278-89.
• [38]Holmskov U, Mollenhauer J, Madsen J, Vitved L, Gronlund J, Tornoe I, et al.: Cloning of gp-340, a putative opsonin receptor for lung surfactant protein D. Proc Natl Acad Sci U S A 1999, 96:10794-9.
• [39]Kang W, Reid KBM: DMBT1, a regulator of mucosal homeostasis through the linking of mucosal defense and regeneration? Febs Letters 2003, 540:21-5.
• [40]Braidotti P, Nuciforo PG, Mollenhauer J, Poustka A, Pellegrini C, Moro A, et al.: DMBT1 expression is down-regulated in breast cancer. BMC Cancer 2004, 4:46. BioMed Central Full Text
• [41]Winkler C, Yao S: The midkine family of growth factors: diverse roles in nervous system formation and maintenance. Br J Pharmacol 2014, 171:905-12.
• [42]Sakamoto K, Kadomatsu K: Midkine in the pathology of cancer, neural disease, and inflammation. Pathol Int 2012, 62:445-55.
• [43]Chen Y, McKenzie KE, Aldaz CM, Sukumar S: Midkine in the progression of rat N-nitroso-N-methylurea-induced mammary tumors. Mol Carcinog 1996, 17:112-6.
• [44]Ibusuki MM, Fujimori HH, Yamamoto YY, Ota KK, Ueda MM, Shinriki SS, et al.: Midkine in plasma as a novel breast cancer marker. Cancer Sci 2009, 100:1735-9.
• [45]Li LQ, Huang HL, Ping JL, Xu W, Li J, Dai LC: Expression of midkine and endoglin in breast carcinomas with different immunohistochemical profiles. APMIS 2011, 119:103-10.
• [46]Hsing CH, Cheng HC, Hsu YH, Chan CH, Yeh CH, Li CF, et al.: Upregulated IL-19 in Breast Cancer Promotes Tumor Progression and Affects Clinical Outcome. Clin Cancer Res 2012, 18:713-25.
• [47]Pichery M, Mirey E, Mercier P, Lefrancais E, Dujardin A, Ortega N, et al.: Endogenous IL-33 Is Highly Expressed in Mouse Epithelial Barrier Tissues, Lymphoid Organs, Brain, Embryos, and Inflamed Tissues: In Situ Analysis Using a Novel Il-33-LacZ Gene Trap Reporter Strain. J Immunol 2012, 188:3488-95.
• [48]Oboki K, Ohno T, Kajiwara N, Arae K, Morita H, Ishii A, et al.: IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc Natl Acad Sci U S A 2010, 107:18581-6.
• [49]Jovanovic IP, Pejnovic NN, Radosavljevic GD, Arsenijevic NN, Lukic ML: IL-33/ST2 axis in innate and acquired immunity to tumors. Oncoimmunology 2012, 1:229-31.
• [50]Lemay DG, Neville MC, Rudolph MC, Pollard KS, German JB: Gene regulatory networks in lactation: identification of global principles using bioinformatics. BMC Syst Biol 2007, 1:56. BioMed Central Full Text
• [51]Anantamongkol U, Charoenphandhu N, Wongdee K, Teerapornpuntakit J, Suthiphongchai T, Prapong S, et al.: Transcriptome analysis of mammary tissues reveals complex patterns of transporter gene expression during pregnancy and lactation. Cell Biol Int 2009, 34:67-74.
• [52]Meier-Abt F, Milani E, Roloff T, Brinkhaus H, Duss S, Meyer DS, et al.: Parity induces differentiation and reduces Wnt/Notch signaling ratio and proliferation potential of basal stem/progenitor cells isolated from mouse mammary epithelium. Breast Cancer Res 2013, 15:R36. BioMed Central Full Text
• [53]Hammond MEH, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al.: American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010, 28:2784-95.
• [54]Smalley MJ: Isolation, culture and analysis of mouse mammary epithelial cells. Methods Mol Biol 2010, 633:139-70.
• [55]Baldi P, Long AD: A Bayesian framework for the analysis of microarray expression data: regularized t -test and statistical inferences of gene changes. Bioinformatics (Oxford, England) 2001, 17:509-19.
• [56]Benjamini Y, Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society. Series B (Methodological) 1995:289–300
• [57]Xiao Y, Hsiao TH, Suresh U, Chen H, Wu X: A novel significance score for gene selection and ranking. Bioinformatics (Oxford, England) 2014, 30:801-7.