{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:09:04Z","timestamp":1760234944370,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,26]],"date-time":"2021-06-26T00:00:00Z","timestamp":1624665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Defense office of the Congressionally Directed Medical Research Program-Breast Cancer Research Program Grant","award":["BC16999"],"award-info":[{"award-number":["BC16999"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Early full-term pregnancy is known to reduce the lifetime risk of breast cancer. Although the phenomenon of parity-induced protection is well-established, the physiological mechanisms involved in this protection are not clear. Earlier reports have shown that pregnancy results in alterations of hormone levels. How pregnancy affects hypothalamic hormones and how the change, if any, influences breast cancer is not well understood. Seven-week-old female Lewis rats were given N-methyl-N-nitrosourea. Two weeks post carcinogen exposure, a set of females were housed with males to generate the parous rats and another set of rats served as the nulliparous controls. Mammary tumorigenesis was assessed for 9 months. Hypothalamic and pituitary levels of hormones were measured at various timepoints. Further, animals were also challenged with growth hormone and prolactin secretagogues to test the effect of pregnancy on the hypothalamic\u2013pituitary hormonal axis. Persistent alterations in the level of growth hormone-releasing hormone, thyrotropin releasing hormone, dopamine, and somatostatin in the hypothalamus of parous animals was observed. Further, we also observed that pregnancy had a significant effect on the pituitary gland and its response to growth hormone and prolactin secretagogues. Our studies using the rodent model system demonstrate that pregnancy could be reducing the risk of breast cancer by persistently altering the hypothalamic\u2013pituitary axis, which could have implications for breast cancers in humans as well.<\/jats:p>","DOI":"10.3390\/cancers13133207","type":"journal-article","created":{"date-parts":[[2021,6,27]],"date-time":"2021-06-27T22:24:57Z","timestamp":1624832697000},"page":"3207","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pregnancy Inhibits Mammary Carcinogenesis by Persistently Altering the Hypothalamic\u2013Pituitary Axis"],"prefix":"10.3390","volume":"13","author":[{"given":"Ramadevi","family":"Subramani","sequence":"first","affiliation":[{"name":"Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"},{"name":"Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriana","family":"Estrada","sequence":"additional","affiliation":[{"name":"Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madeline","family":"Dixon","sequence":"additional","affiliation":[{"name":"Paul L Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Parada","sequence":"additional","affiliation":[{"name":"Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheryl","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7355-2952","authenticated-orcid":false,"given":"Diego A.","family":"Pedroza","sequence":"additional","affiliation":[{"name":"Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew D.","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Paul L Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexa","family":"Clift","sequence":"additional","affiliation":[{"name":"Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lilia","family":"Garcia","sequence":"additional","affiliation":[{"name":"Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajkumar","family":"Lakshmanaswamy","sequence":"additional","affiliation":[{"name":"Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"},{"name":"Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/bs.pmbts.2017.07.006","article-title":"Pregnancy and Breast Cancer","volume":"151","author":"Subramani","year":"2017","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1007\/s10549-020-05804-1","article-title":"Parity reduces mammary repopulating activity but does not affect mammary stem cells defined as CD24\u2009+\u2009CD29\/CD49fhi in mice","volume":"183","author":"Dall","year":"2020","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_3","first-page":"209","article-title":"Age at first birth and breast cancer risk","volume":"43","author":"MacMahon","year":"1970","journal-title":"Bull. World Health Organ."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1093\/jnci\/53.3.609","article-title":"An epidemiologic study of breast cancer","volume":"53","author":"Henderson","year":"1974","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1093\/oxfordjournals.aje.a114594","article-title":"Breast cancer risk associated with proliferative disease, age at first birth, and a family history of breast cancer","volume":"125","author":"Dupont","year":"1987","journal-title":"Am. J. Epidemiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1093\/oxfordjournals.epirev.a036112","article-title":"Breast cancer epidemiology: Summary and future directions","volume":"15","author":"Kelsey","year":"1993","journal-title":"Epidemiol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1093\/carcin\/16.11.2847","article-title":"Refractoriness to mammary tumorigenesis in parous rats: Is it caused by persistent changes in the hormonal environment or permanent biochemical alterations in the mammary epithelia?","volume":"16","author":"Thordarson","year":"1995","journal-title":"Carcinogenesis"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1002\/ijc.2910040308","article-title":"Relationship between previous reproductive history and chemically induced mammary cancer in rats","volume":"4","author":"Moon","year":"1969","journal-title":"Int. J. Cancer J. Int. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1159\/000363017","article-title":"Parity and short-term estradiol treatment utilizes similar cellular mechanisms to confer protection against breast cancer","volume":"34","author":"Arumugam","year":"2014","journal-title":"Cell Physiol. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1046\/j.1524-4741.2001.21033.x","article-title":"Mammary gland architecture as a determining factor in the susceptibility of the human breast to cancer","volume":"7","author":"Russo","year":"2001","journal-title":"Breast J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/0304-3835(94)03681-8","article-title":"The etiopathogenesis of breast cancer prevention","volume":"90","author":"Russo","year":"1995","journal-title":"Cancer Lett."},{"key":"ref_12","first-page":"353","article-title":"Toward a physiological approach to breast cancer prevention","volume":"3","author":"Russo","year":"1994","journal-title":"Cancer Epidemiol. Biomark. Prev. Publ. Am. Assoc. Cancer Res. Cosponsored Am. Soc. Prev. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"R20","DOI":"10.1186\/bcr2245","article-title":"Pregnancy in the mature adult mouse does not alter the proportion of mammary epithelial stem\/progenitor cells","volume":"11","author":"Britt","year":"2009","journal-title":"Breast Cancer Res. BCR"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/sj.onc.1208185","article-title":"Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-beta1 expression","volume":"24","author":"Boulanger","year":"2005","journal-title":"Oncogene"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"151","DOI":"10.2741\/1788","article-title":"The concept of stem cell in the mammary gland and its implication in morphogenesis, cancer and prevention","volume":"11","author":"Russo","year":"2006","journal-title":"Front. Biosci. J. Virtual Libr."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Nandy, S.B., Subramani, R., Rajamanickam, V., Lopez-Valdez, R., Arumugam, A., Boopalan, T., and Lakshmanaswamy, R. (2014). microRNA alterations in ALDH positive mammary epithelial cells: A crucial contributing factor towards breast cancer risk reduction in case of early pregnancy. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-644"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2390","DOI":"10.1016\/j.ejca.2006.03.027","article-title":"Immunocytochemical localisation of plasma membrane GHRH receptors in human tumours using a novel anti-peptide antibody","volume":"42","author":"Schulz","year":"2006","journal-title":"Eur. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1002\/dta.2953","article-title":"The intra-individual stability of GH biomarkers IGF-I and P-III-NP in relation to GHRH administration, menstrual cycle, and hematological parameters","volume":"12","author":"Ericsson","year":"2020","journal-title":"Drug Test. Anal."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111098","DOI":"10.1016\/j.mce.2020.111098","article-title":"Mice with an RGS-insensitive G\u03b1","volume":"521","author":"Omouessi","year":"2021","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"106536","DOI":"10.1016\/j.domaniend.2020.106536","article-title":"Plasma prolactin, thyroid-stimulating hormone, melanocyte-stimulating hormone, and adrenocorticotropin responses to thyrotropin-releasing hormone in mares treated with detomidine and butorphanol","volume":"74","author":"Oberhaus","year":"2021","journal-title":"Domest. Anim. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e12884","DOI":"10.1111\/jne.12884","article-title":"Morphological plasticity of the tuberoinfundibular dopaminergic neurones in the rat during the oestrous cycle and lactation","volume":"32","author":"Yip","year":"2020","journal-title":"J. Neuroendocr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12033","DOI":"10.3168\/jds.2019-18087","article-title":"Suppression of prolactin and reduction of milk secretion by effect of cabergoline in lactating dairy ewes","volume":"103","author":"Caja","year":"2020","journal-title":"J. Dairy Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1159\/000438533","article-title":"A Breast Tissue Protein Expression Profile Contributing to Early Parity-Induced Protection Against Breast Cancer","volume":"37","author":"Gutierrez","year":"2015","journal-title":"Cell Physiol. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"82538","DOI":"10.18632\/oncotarget.12757","article-title":"The serum protein profile of early parity which induces protection against breast cancer","volume":"7","author":"Bracamontes","year":"2016","journal-title":"Oncotarget"},{"key":"ref_25","first-page":"50","article-title":"Nutrition of French adolescents. Current views","volume":"111\u2013112","author":"Baudier","year":"1990","journal-title":"Soins Gynecol. Obs. Pueric. Pediatr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1210\/me.2010-0255","article-title":"Growth hormone signaling in human T47D breast cancer cells: Potential role for a growth hormone receptor-prolactin receptor complex","volume":"25","author":"Xu","year":"2011","journal-title":"Mol. Endocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-018-0197-8","article-title":"Silencing growth hormone receptor inhibits estrogen receptor negative breast cancer through ATP-binding cassette sub-family G member 2","volume":"51","author":"Arumugam","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1055\/s-2007-1013563","article-title":"Elevated growth hormone levels in sera from breast cancer patients","volume":"17","author":"Emerman","year":"1985","journal-title":"Horm. Metab. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/j.1365-2265.2005.02404.x","article-title":"Does growth hormone cause cancer?","volume":"64","author":"Jenkins","year":"2006","journal-title":"Clin. Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.ghir.2006.10.007","article-title":"Patients with congenital deficiency of IGF-I seem protected from the development of malignancies: A preliminary report","volume":"17","author":"Shevah","year":"2007","journal-title":"Growth Horm. IGF Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1093\/carcin\/23.6.977","article-title":"The growth hormone-deficient Spontaneous Dwarf rat is resistant to chemically induced mammary carcinogenesis","volume":"23","author":"Swanson","year":"2002","journal-title":"Carcinogenesis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s10549-004-9504-2","article-title":"Mammary tumorigenesis in growth hormone deficient spontaneous dwarf rats; effects of hormonal treatments","volume":"87","author":"Thordarson","year":"2004","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"bqab013","DOI":"10.1210\/endocr\/bqab013","article-title":"Mammary Tumors Growing in the Absence of Growth Hormone Are More Sensitive to Doxorubicin Than Wild-Type Tumors","volume":"162","author":"Lantvit","year":"2021","journal-title":"Endocrinology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"598423","DOI":"10.3389\/fphar.2020.598423","article-title":"Preparation of a Growth Hormone Receptor\/Prolactin Receptor Bispecific Antibody Antagonist Which Exhibited Anti-Cancer Activity","volume":"11","author":"Chen","year":"2020","journal-title":"Front. Pharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1158\/1940-6207.CAPR-09-0074","article-title":"Parity-induced decrease in systemic growth hormone alters mammary gland signaling: A potential role in pregnancy protection from breast cancer","volume":"3","author":"Dearth","year":"2010","journal-title":"Cancer Prev. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s10911-008-9063-y","article-title":"Prolactin and breast cancer etiology: An epidemiologic perspective","volume":"13","author":"Tworoger","year":"2008","journal-title":"J. Mammary Gland Biol. Neoplasia"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/0304-3835(95)03712-6","article-title":"Refractoriness to mammary carcinogenesis in the parous mouse is reversible by hormonal stimulation induced by pituitary isografts","volume":"90","author":"Swanson","year":"1995","journal-title":"Cancer Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1093\/carcin\/bgp120","article-title":"Prolactin confers resistance against cisplatin in breast cancer cells by activating glutathione-S-transferase","volume":"30","author":"LaPensee","year":"2009","journal-title":"Carcinogenesis"},{"key":"ref_39","first-page":"654","article-title":"Platinum agents in the treatment of early-stage triple-negative breast cancer: Is it time to change practice?","volume":"12","author":"Agrawal","year":"2014","journal-title":"Clin. Adv. Hematol. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3165","DOI":"10.1158\/0008-5472.CAN-08-4033","article-title":"Impaired turnover of prolactin receptor contributes to transformation of human breast cells","volume":"69","author":"Plotnikov","year":"2009","journal-title":"Cancer Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/13\/3207\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:25:01Z","timestamp":1760163901000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/13\/3207"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,26]]},"references-count":40,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["cancers13133207"],"URL":"https:\/\/doi.org\/10.3390\/cancers13133207","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2021,6,26]]}}}