ABSTRACT
PTEN is one of the most commonly inactivated tumour suppressor genes in sporadic cancer. Germline heterozygous PTEN gene alterations also underlie PTEN hamartoma tumour syndrome (PHTS), a rare human cancer-predisposition condition. A key feature of systemic PTEN deregulation is the inability to adequately dampen PI3-kinase (PI3K)/mTORC1 signalling. PI3K/mTORC1 pathway inhibitors such as rapamycin are therefore expected to neutralise the impact of PTEN loss, rendering this a more druggable context compared with those of other tumour suppressor pathways such as loss of TP53. However, this has not been explored in cancer prevention in a model of germline cancer predisposition, such as PHTS. Clinical trials of short-term treatment with rapamycin have recently been initiated for PHTS, focusing on cognition and colon polyposis. Here, we administered a low dose of rapamycin from the age of 6 weeks onwards to mice with heterozygous germline Pten loss, a mouse model that recapitulates most characteristics of human PHTS. Rapamycin was well tolerated and led to a highly significant improvement of survival in both male and female mice. This was accompanied by a delay in, but not full blockade of, the development of a range of proliferative lesions, including gastro-intestinal and thyroid tumours and endometrial hyperplasia, with no impact on mammary and prostate tumours, and no effect on brain overgrowth. Our data indicate that rapamycin may have cancer prevention potential in human PHTS. This might also be the case for sporadic cancers in which genetic PI3K pathway activation is an early event in tumour development, such as endometrial cancer and some breast cancers. To the best of our knowledge, this is the first report of a long-term treatment of a germline cancer predisposition model with a PI3K/mTOR pathway inhibitor. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Subject(s)
Hamartoma Syndrome, Multiple , Thyroid Neoplasms , Mice , Animals , Male , Female , Humans , Infant , Sirolimus/pharmacology , Sirolimus/therapeutic use , Phosphatidylinositol 3-Kinases/genetics , Longevity , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Hamartoma Syndrome, Multiple/drug therapy , Hamartoma Syndrome, Multiple/genetics , Hamartoma Syndrome, Multiple/pathology , Phosphatidylinositol 3-Kinase/genetics , Phosphoinositide-3 Kinase Inhibitors , Mechanistic Target of Rapamycin Complex 1/genetics , Germ Cells/metabolism , Germ-Line MutationABSTRACT
Maternal guilt has been a longstanding concern for mothers in the Western world. Literature around mother's experiences of maternal guilt has allowed researchers to understand maternal guilt from a mother's perspective. In this paper the authors aimed to systematically review this literature, to declare a more unified understanding of what the experience of maternal guilt is, from a mother's perspective, and what role the "motherhood myth" has in maternal experiences of guilt. Our thematic analysis found the following themes relating to maternal guilt experiences: the motherhood myth, breastfeeding difficulties, essentialism/responsibility, division/depletion and connection. The motherhood myth was present in all the included articles, providing an unattainable ideal of motherhood from which mothers compare themselves and their actions to, contributing to their sense of maternal guilt. Mothers experienced many difficulties in their mothering roles, including difficulty breastfeeding, feeling a great sense of responsibility to their child, feeling divided in wanting to take time for themselves and depleted in having many tasks to complete and coping with a multitude of emotions, and feeling a profound sense of connection to their child(ren), which was experienced as both positive and negative.
