The human intermediate prolactin receptor is a mammary proto-oncogene
Abstract The hormone prolactin (PRL) and its receptor (hPRLr) are significantly involved in breast cancer pathogenesis. The intermediate hPRLr (hPRLrI) is an alternatively-spliced isoform, capable of stimulating cellular viability and proliferation. An analogous truncated mouse PRLr (mPRLr) was rece...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-03-01
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| Series: | npj Breast Cancer |
| Online Access: | https://doi.org/10.1038/s41523-021-00243-7 |
| _version_ | 1797428084219052032 |
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| author | Jacqueline M. Grible Patricija Zot Amy L. Olex Shannon E. Hedrick J. Chuck Harrell Alicia E. Woock Michael O. Idowu Charles V. Clevenger |
| author_facet | Jacqueline M. Grible Patricija Zot Amy L. Olex Shannon E. Hedrick J. Chuck Harrell Alicia E. Woock Michael O. Idowu Charles V. Clevenger |
| author_sort | Jacqueline M. Grible |
| collection | DOAJ |
| description | Abstract The hormone prolactin (PRL) and its receptor (hPRLr) are significantly involved in breast cancer pathogenesis. The intermediate hPRLr (hPRLrI) is an alternatively-spliced isoform, capable of stimulating cellular viability and proliferation. An analogous truncated mouse PRLr (mPRLr) was recently found to be oncogenic when co-expressed with wild-type mPRLr. The goal of this study was to determine if a similar transforming event occurs with the hPRLr in human breast epithelial cells and to better understand the mechanism behind such transformation. hPRLrL+I co-expression in MCF10AT cells resulted in robust in vivo and in vitro transformation, while hPRLrI knock-down in MCF7 cells significantly decreased in vitro malignant potential. hPRLrL+I heterodimers displayed greater stability than hPRLrL homodimers, and while being capable of activating Jak2, Ras, and MAPK, they were unable to induce Stat5a tyrosine phosphorylation. Both immunohistochemical breast cancer tissue microarray data and RNA sequencing analyses using The Cancer Genome Atlas (TCGA) identified that higher hPRLrI expression associates with triple-negative breast cancer. These studies indicate the hPRLrI, when expressed alongside hPRLrL, participates in mammary transformation, and represents a novel oncogenic mechanism. |
| first_indexed | 2024-03-09T08:54:06Z |
| format | Article |
| id | doaj.art-4c18855c6cd74555a97c5428cf615799 |
| institution | Directory Open Access Journal |
| issn | 2374-4677 |
| language | English |
| last_indexed | 2024-03-09T08:54:06Z |
| publishDate | 2021-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Breast Cancer |
| spelling | doaj.art-4c18855c6cd74555a97c5428cf6157992023-12-02T13:35:58ZengNature Portfolionpj Breast Cancer2374-46772021-03-017111110.1038/s41523-021-00243-7The human intermediate prolactin receptor is a mammary proto-oncogeneJacqueline M. Grible0Patricija Zot1Amy L. Olex2Shannon E. Hedrick3J. Chuck Harrell4Alicia E. Woock5Michael O. Idowu6Charles V. Clevenger7Department of Pathology and Massey Cancer Center, Virginia Commonwealth UniversityDepartment of Pathology and Massey Cancer Center, Virginia Commonwealth UniversityWright Center for Clinical and Translational Research, Virginia Commonwealth UniversityDepartment of Pathology and Massey Cancer Center, Virginia Commonwealth UniversityDepartment of Pathology and Massey Cancer Center, Virginia Commonwealth UniversityDepartment of Pathology and Massey Cancer Center, Virginia Commonwealth UniversityDepartment of Pathology and Massey Cancer Center, Virginia Commonwealth UniversityDepartment of Pathology and Massey Cancer Center, Virginia Commonwealth UniversityAbstract The hormone prolactin (PRL) and its receptor (hPRLr) are significantly involved in breast cancer pathogenesis. The intermediate hPRLr (hPRLrI) is an alternatively-spliced isoform, capable of stimulating cellular viability and proliferation. An analogous truncated mouse PRLr (mPRLr) was recently found to be oncogenic when co-expressed with wild-type mPRLr. The goal of this study was to determine if a similar transforming event occurs with the hPRLr in human breast epithelial cells and to better understand the mechanism behind such transformation. hPRLrL+I co-expression in MCF10AT cells resulted in robust in vivo and in vitro transformation, while hPRLrI knock-down in MCF7 cells significantly decreased in vitro malignant potential. hPRLrL+I heterodimers displayed greater stability than hPRLrL homodimers, and while being capable of activating Jak2, Ras, and MAPK, they were unable to induce Stat5a tyrosine phosphorylation. Both immunohistochemical breast cancer tissue microarray data and RNA sequencing analyses using The Cancer Genome Atlas (TCGA) identified that higher hPRLrI expression associates with triple-negative breast cancer. These studies indicate the hPRLrI, when expressed alongside hPRLrL, participates in mammary transformation, and represents a novel oncogenic mechanism.https://doi.org/10.1038/s41523-021-00243-7 |
| spellingShingle | Jacqueline M. Grible Patricija Zot Amy L. Olex Shannon E. Hedrick J. Chuck Harrell Alicia E. Woock Michael O. Idowu Charles V. Clevenger The human intermediate prolactin receptor is a mammary proto-oncogene npj Breast Cancer |
| title | The human intermediate prolactin receptor is a mammary proto-oncogene |
| title_full | The human intermediate prolactin receptor is a mammary proto-oncogene |
| title_fullStr | The human intermediate prolactin receptor is a mammary proto-oncogene |
| title_full_unstemmed | The human intermediate prolactin receptor is a mammary proto-oncogene |
| title_short | The human intermediate prolactin receptor is a mammary proto-oncogene |
| title_sort | human intermediate prolactin receptor is a mammary proto oncogene |
| url | https://doi.org/10.1038/s41523-021-00243-7 |
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