Human relevance of rodent prolactin-induced non-genotoxic mammary carcinogenesis: prolactin involvement in human breast cancer and significance for toxicology risk assessments.
Prolactin-induced mammary carcinogenesis in rodents, particularly rats, is often stated to be of low toxicological relevance to humans. This opinion appears to have developed from a number of lines of cited evidence. Firstly, there had been long experience of use of dopamine antagonists (that increase prolactin) in human medicine and no evidence of an increase in breast cancer incidence or risk had been reported. Secondly, dopamine agonists (that lower prolactin) had been shown to have no effect in human breast cancer treatment. Thirdly, the actions of prolactin were considered different between rodents and humans. However, recent evidence now suggests that prolactin has a major role in human breast cancer, and the similarity of mechanism with the rodent suggests that prolactin-mediated mammary carcinogenesis in rodents could be of much higher toxicological relevance to humans than previously thought. Large epidemiology studies have upgraded a limited database and shown that dopamine antagonists (both antipsychotics and anti-emetics) increase breast cancer risk, that hyperprolactinaemia is consistently associated with human breast cancer growth, development and poor prognosis, and that prolactin is indeed a mitogen in human breast cancer cells that suppresses apoptosis and upregulates BRCA1. It is now clear that initial studies giving dopamine agonists to breast cancer patients had no effect because breast cancer cells also produced prolactin independently of the pituitary, which remained uncontrolled and unrecognized in early clinical studies. The evidence for the role of prolactin in human breast cancer is now strong and consistent, and is discussed and related to the risk assessment of drugs and chemicals. The conclusion is that it is invalid to suggest that prolactin-induced mammary carcinogenesis in rodents is of low relevance to humans because prolactin can induce an adverse response in the mammary tissue of both rodents and humans alike. Drugs and chemicals causing rodent prolactin-induced mammary carcinogenesis may therefore pose a risk to humans via the same mechanism if exposures also increase prolactin secretion in humans.
Harvey
Philip W
PW
Department of Toxicology, Covance Laboratories, Otley Road, Harrogate, North Yorkshire HG3 1PY, UK. philip.harvey@covance.com
D000818:Animals; D001943:Breast Neoplasms / Q000139:chemically induced*; D018492:Dopamine Antagonists / Q000009:adverse effects*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced*; D051379:Mice; D008875:Middle Aged; D017698:Postmenopause; D011388:Prolactin / Q000009:adverse effects* / Q000633:toxicity; D051381:Rats; D018570:Risk Assessment
D018492:Dopamine Antagonists; D011388:Prolactin