Human relevance of rodent prolactin-induced non-genotoxic mammary carcinogenesis: prolactin involvement in human breast cancer and significance for toxicology risk assessments

Harvey, Philip W.

doi:10.1002/jat.1063

Cited by 32 publications

(29 citation statements)

References 37 publications

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“…8 As a result, loss of PR in the course of malignant transformation and cancer progression reflects a nonfunctional nuclear expression of ERa. 1,16 In our study, nonfunctional ERa expression is therefore hypothesized for those PR-negative mammary adenocarcinomas with a typical ERa nuclear expression. This hypothesis will need to be biologically tested by transplantation of relevant tumors.…”

Section: Discussionmentioning

confidence: 83%

Mammary Tumor Phenotypes in Wild-Type Aging Female FVB/N Mice with Pituitary Prolactinomas

Radælli¹,

Arnold

Παπανικολάου

et al. 2009

Vet Pathol

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Abstract. Prolactin-secreting pituitary adenomas are common spontaneous lesions in aging FVB females. Prolactin-secreting pituitary proliferations play a significant role in mouse mammary tumorigenesis generally producing adenosquamous carcinomas. Since genetically engineered FVB mice are frequently used to study mammary tumor biology, we have examined a cohort of 64 aging wild-type FVB/N females to establish the prevalence and the nature of spontaneous mammary and pituitary tumors. Tissues from mammary and pituitary glands were studied by histopathology and immunohistochemistry. Of the 64 examined mice, 20 had pituitary tumors and 20 had mammary tumors. Mammary and pituitary tumors were associated in 17 mice. All pituitary tumors were prolactinpositive by immunohistochemistry and classified as prolactinomas. Fourteen mammary tumors, including 12 cases with and 2 without concurrent prolactinomas, were adenocarcinomas with different combinations of epithelial growth patterns. Five mice with prolactinomas had mammary tumors characterized by the epithelial-mesenchymal transition (EMT) phenotype. Estrogen receptor alpha (ERa)-positivity was observed for 14 of the 18 mammary tumors tested, including both adenocarcinomas with nuclear immunoreactivity and EMT-phenotype tumors with both nuclear and cytoplasmic immunoreactivity. No immunoreactivity for the progesterone receptor was observed. This study confirms that spontaneous prolactinomas and mammary tumors are both common and significantly associated lesions in FVB mice. Parity and age represented risk factors for the development of these tumors. Compared with previous reports, prolactinoma-associated mammary tumors displayed a broader morphologic spectrum, including cases with the EMT phenotype. The elevated number of prolactinoma-associated and ERa-positive mammary tumors opens intriguing possibilities concerning the role of ERa cytoplasmic localization during EMT tumorigenesis.

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Section: Discussionmentioning

confidence: 83%

Mammary Tumor Phenotypes in Wild-Type Aging Female FVB/N Mice with Pituitary Prolactinomas

Radælli¹,

Arnold

Παπανικολάου

et al. 2009

Vet Pathol

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“…The argument that prolactin is not important in human breast cancer has been influential in regulatory processes, 74,82,83 despite the fact that somewhat limited data support this hypothesis. 72 New data derived from the study of dopamine antagonists and breast cancer shows that prolactin plays an important role in human breast cancer and suggests that prolactin-mediated mammary carcinogenesis in rodents may be relevant to humans. 72 …”

Section: Rodent/human Hormonal Differencesmentioning

confidence: 99%

“…72 New data derived from the study of dopamine antagonists and breast cancer shows that prolactin plays an important role in human breast cancer and suggests that prolactin-mediated mammary carcinogenesis in rodents may be relevant to humans. 72 …”

Section: Rodent/human Hormonal Differencesmentioning

confidence: 99%

Chemicals causing mammary gland tumors in animals signal new directions for epidemiology, chemicals testing, and risk assessment for breast cancer prevention

Rudel

Attfield

Schifano

et al. 2007

Cancer

184

191

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Identifying chemical carcinogens in animal studies is currently the primary means of anticipating cancer effects in humans. Animal studies to evaluate potential chemical carcinogenicity are particularly important for breast cancer because environmental and occupational epidemiologic research is sparse.Chemicals that increased mammary gland tumors in animal studies were compiled from the International Agency for Research on Cancer (IARC), the U.S. National Toxicology Program (NTP), and other sources. Summary assessments of the carcinogenic potential for each chemical and potentially exposed populations were also compiled. In all, 216 chemicals were identified that have been associated with increases in mammary gland tumors in at least 1 study. These include industrial chemicals, chlorinated solvents, products of combustion, pesticides, dyes, radiation, drinking water disinfection byproducts, pharmaceuticals and hormones, natural products, and research chemicals. Twenty-nine are produced in the U.S. at >1 million pounds/year; 35 are air pollutants, 25 have involved occupational exposures to >5000 women, and 73 have been present in consumer products or as contaminants of food. Thus, exposure is widespread. Nearly all of the chemicals were mutagenic and most caused tumors in multiple organs and species; these characteristics are generally believed to indicate likely carcinogenicity in humans. To our knowledge, this is the most comprehensive list developed of animal mammary gland carcinogens and, along with associated data, is publicly available at URL: www.silentspring.org/sciencereview and at URL: www.komen. org/environment. Valuable information from cancer bioassays is not well utilized in risk assessment and regulatory processes, suggesting a need to strengthen chemicals testing and risk assessment as tools for breast cancer prevention.

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“…PRL is a major factor in the proliferation and differentiation of breast epithelium and is the primary hormone in the stimulation and maintenance of lactation. It is also a tumor promoter in rodents and has been implicated in the development of breast cancer (5). The human PRLR (hPRLR) has several forms, including a long form and several short forms, which are products of alternative splicing with variable lengths in their cytoplasmic domains containing some unique sequences (8,9).…”

mentioning

confidence: 99%

Complex Formation and Interactions between Transcription Factors Essential for Human Prolactin Receptor Gene Transcription

Kang

Tsai‐Morris

Dufau

2011

Molecular and Cellular Biology

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The prolactin receptor (PRLR) is a member of the lactogen/ cytokine receptor family which mediates the diverse cellular actions of prolactin (PRL) in several target tissues. PRL is a major factor in the proliferation and differentiation of breast epithelium and is the primary hormone in the stimulation and maintenance of lactation. It is also a tumor promoter in rodents and has been implicated in the development of breast cancer (5). The human PRLR (hPRLR) has several forms, including a long form and several short forms, which are products of alternative splicing with variable lengths in their cytoplasmic domains containing some unique sequences (8, 9). The short forms S1a and S1b are dominant-negative repressors of the function of homodimers of the PRLR long form that mediates all known stimulatory functions of PRL through the Jak-2/Stat5 signaling pathway. The dominant-negative effect of the short forms results from their heterodimerization with the long form, leading to inactivation due to the lack of required cytoplasmic sequences for STAT signaling activation (23, 29). Intramolecular S-S bonds in the extracellular domain of the PRLR short forms were found to be required for their inhibitory action on PRL-induced PRLR long form-mediated STAT5-dependent action (29). The PRLR forms are expressed in normal and tumoral breast tissue, in most human breast cancer cells, and in several other tissues (8,17,19). In humans, hPRLR expression is controlled by a complex regulatory system at the transcriptional level which is governed by multiple promoters. These include the preferentially utilized generic promoter 1/exon 1 (PIII/hEI3), which also is present in rat and mouse, and five human-specific exon 1 promoters (hE1N1 to hE1N5) (11, 12). These promoters were found to be utilized in breast cancer tissue and cell lines, including MCF7 and T47D, and variably in other tissues (12). Among these promoters, the preferentially utilized human promoter III (hPIII), the human counterpart of rodent PIII, was functionally characterized in breast cancer cells. 17␤-Estradiol (E2) induced an increase in PRLR mRNA transcripts directed by the preferentially utilized hPIII promoter. Also, in transfection studies E2 activated the hPIII promoter, which lacks an estrogen response element (ERE) (16). This promoter contains functional SP1 and C/EBP␤ elements that bind SP1/SP3 and C/EBP␤, respectively (10, 12). The abolition of the E2 effect by the mutation of SP1 and C/EBP␤ elements within PIII indicated the cooperation in E2-induced transcription of hPRLR. E2 regulates PRLR expression through a nonclassical ERE-independent mechanism in target cells. The E2/estrogen receptor ␣ (ER␣) complex translocates to the nucleus and binds transfactors at the hPIII promoter, leading to the recruitment of coactivators (p300, SRC-1, and pCAF) to the complex with consequent region-specific changes in histone acetylation. These hormone/receptor-induced associations and chromatin changes favored TFIIB and RNA polymerase II recruitment, leading to the activa...

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Human relevance of rodent prolactin-induced non-genotoxic mammary carcinogenesis: prolactin involvement in human breast cancer and significance for toxicology risk assessments

Cited by 32 publications

References 37 publications

Mammary Tumor Phenotypes in Wild-Type Aging Female FVB/N Mice with Pituitary Prolactinomas

Mammary Tumor Phenotypes in Wild-Type Aging Female FVB/N Mice with Pituitary Prolactinomas

Chemicals causing mammary gland tumors in animals signal new directions for epidemiology, chemicals testing, and risk assessment for breast cancer prevention

Complex Formation and Interactions between Transcription Factors Essential for Human Prolactin Receptor Gene Transcription

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