Co-administering Melatonin With an Estradiol-Progesterone Menopausal Hormone Therapy Represses Mammary Cancer Development in a Mouse Model of HER2-Positive Breast Cancer
Melatonin has numerous anti-cancer properties reported to influence cancer initiation, promotion, and metastasis. With the need for effective hormone therapies (HT) to treat menopausal symptoms without increasing breast cancer risk, co-administration of nocturnal melatonin with a natural, low-dose H...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-07-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2019.00525/full |
| _version_ | 1818014563324395520 |
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| author | Balasunder R. Dodda Corry D. Bondi Mahmud Hasan William P. Clafshenkel Katie M. Gallagher Mary P. Kotlarczyk Shalini Sethi Ethan Buszko Jean J. Latimer J. Mark Cline Paula A. Witt-Enderby Paula A. Witt-Enderby Vicki L. Davis |
| author_facet | Balasunder R. Dodda Corry D. Bondi Mahmud Hasan William P. Clafshenkel Katie M. Gallagher Mary P. Kotlarczyk Shalini Sethi Ethan Buszko Jean J. Latimer J. Mark Cline Paula A. Witt-Enderby Paula A. Witt-Enderby Vicki L. Davis |
| author_sort | Balasunder R. Dodda |
| collection | DOAJ |
| description | Melatonin has numerous anti-cancer properties reported to influence cancer initiation, promotion, and metastasis. With the need for effective hormone therapies (HT) to treat menopausal symptoms without increasing breast cancer risk, co-administration of nocturnal melatonin with a natural, low-dose HT was evaluated in mice that develop primary and metastatic mammary cancer. Individually, melatonin (MEL) and estradiol-progesterone therapy (EPT) did not significantly affect mammary cancer development through age 14 months, but, when combined, the melatonin-estradiol-progesterone therapy (MEPT) significantly repressed tumor formation. This repression was due to effects on tumor incidence, but not latency. These results demonstrate that melatonin and the HT cooperate to decrease the mammary cancer risk. Melatonin and EPT also cooperate to alter the balance of the progesterone receptor (PR) isoforms by significantly increasing PRA protein expression only in MEPT mammary glands. Melatonin significantly suppressed amphiregulin transcripts in MEL and MEPT mammary glands, suggesting that amphiregulin together with the higher PRA:PRB balance and other factors may contribute to reducing cancer development in MEPT mice. Melatonin supplementation influenced mammary morphology by increasing tertiary branching in the mouse mammary glands and differentiation in human mammary epithelial cell cultures. Uterine weight in the luteal phase was elevated after long-term exposure to EPT, but not to MEPT, indicating that melatonin supplementation may reduce estrogen-induced uterine stimulation. Melatonin supplementation significantly decreased the incidence of grossly-detected lung metastases in MEL mice, suggesting that melatonin delays the formation of metastatic lesions and/or decreases aggressiveness in this model of HER2+ breast cancer. Mammary tumor development was similar in EPT and MEPT mice until age 8.6 months, but after 8.6 months, only MEPT continued to suppress cancer development. These data suggest that melatonin supplementation has a negligible effect in young MEPT mice, but is required in older mice to inhibit tumor formation. Since melatonin binding was significantly decreased in older mammary glands, irrespective of treatment, melatonin supplementation may overcome reduced melatonin responsiveness in the aged MEPT mice. Since melatonin levels are known to decline near menopause, nocturnal melatonin supplementation may also be needed in aging women to cooperate with HT to decrease breast cancer risk. |
| first_indexed | 2024-04-14T06:47:03Z |
| format | Article |
| id | doaj.art-e13e4dff708f404a8d1805f40f6dd9cf |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-14T06:47:03Z |
| publishDate | 2019-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-e13e4dff708f404a8d1805f40f6dd9cf2022-12-22T02:07:09ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2019-07-01910.3389/fonc.2019.00525464883Co-administering Melatonin With an Estradiol-Progesterone Menopausal Hormone Therapy Represses Mammary Cancer Development in a Mouse Model of HER2-Positive Breast CancerBalasunder R. Dodda0Corry D. Bondi1Mahmud Hasan2William P. Clafshenkel3Katie M. Gallagher4Mary P. Kotlarczyk5Shalini Sethi6Ethan Buszko7Jean J. Latimer8J. Mark Cline9Paula A. Witt-Enderby10Paula A. Witt-Enderby11Vicki L. Davis12Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United StatesGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United StatesGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United StatesGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United StatesGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United StatesGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United StatesGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United StatesGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United StatesUPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United StatesDepartment of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, United StatesGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United StatesUPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United StatesGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United StatesMelatonin has numerous anti-cancer properties reported to influence cancer initiation, promotion, and metastasis. With the need for effective hormone therapies (HT) to treat menopausal symptoms without increasing breast cancer risk, co-administration of nocturnal melatonin with a natural, low-dose HT was evaluated in mice that develop primary and metastatic mammary cancer. Individually, melatonin (MEL) and estradiol-progesterone therapy (EPT) did not significantly affect mammary cancer development through age 14 months, but, when combined, the melatonin-estradiol-progesterone therapy (MEPT) significantly repressed tumor formation. This repression was due to effects on tumor incidence, but not latency. These results demonstrate that melatonin and the HT cooperate to decrease the mammary cancer risk. Melatonin and EPT also cooperate to alter the balance of the progesterone receptor (PR) isoforms by significantly increasing PRA protein expression only in MEPT mammary glands. Melatonin significantly suppressed amphiregulin transcripts in MEL and MEPT mammary glands, suggesting that amphiregulin together with the higher PRA:PRB balance and other factors may contribute to reducing cancer development in MEPT mice. Melatonin supplementation influenced mammary morphology by increasing tertiary branching in the mouse mammary glands and differentiation in human mammary epithelial cell cultures. Uterine weight in the luteal phase was elevated after long-term exposure to EPT, but not to MEPT, indicating that melatonin supplementation may reduce estrogen-induced uterine stimulation. Melatonin supplementation significantly decreased the incidence of grossly-detected lung metastases in MEL mice, suggesting that melatonin delays the formation of metastatic lesions and/or decreases aggressiveness in this model of HER2+ breast cancer. Mammary tumor development was similar in EPT and MEPT mice until age 8.6 months, but after 8.6 months, only MEPT continued to suppress cancer development. These data suggest that melatonin supplementation has a negligible effect in young MEPT mice, but is required in older mice to inhibit tumor formation. Since melatonin binding was significantly decreased in older mammary glands, irrespective of treatment, melatonin supplementation may overcome reduced melatonin responsiveness in the aged MEPT mice. Since melatonin levels are known to decline near menopause, nocturnal melatonin supplementation may also be needed in aging women to cooperate with HT to decrease breast cancer risk.https://www.frontiersin.org/article/10.3389/fonc.2019.00525/fullbreast cancerestradiolHER2/Neumelatoninmenopausal hormone therapymetastasis |
| spellingShingle | Balasunder R. Dodda Corry D. Bondi Mahmud Hasan William P. Clafshenkel Katie M. Gallagher Mary P. Kotlarczyk Shalini Sethi Ethan Buszko Jean J. Latimer J. Mark Cline Paula A. Witt-Enderby Paula A. Witt-Enderby Vicki L. Davis Co-administering Melatonin With an Estradiol-Progesterone Menopausal Hormone Therapy Represses Mammary Cancer Development in a Mouse Model of HER2-Positive Breast Cancer Frontiers in Oncology breast cancer estradiol HER2/Neu melatonin menopausal hormone therapy metastasis |
| title | Co-administering Melatonin With an Estradiol-Progesterone Menopausal Hormone Therapy Represses Mammary Cancer Development in a Mouse Model of HER2-Positive Breast Cancer |
| title_full | Co-administering Melatonin With an Estradiol-Progesterone Menopausal Hormone Therapy Represses Mammary Cancer Development in a Mouse Model of HER2-Positive Breast Cancer |
| title_fullStr | Co-administering Melatonin With an Estradiol-Progesterone Menopausal Hormone Therapy Represses Mammary Cancer Development in a Mouse Model of HER2-Positive Breast Cancer |
| title_full_unstemmed | Co-administering Melatonin With an Estradiol-Progesterone Menopausal Hormone Therapy Represses Mammary Cancer Development in a Mouse Model of HER2-Positive Breast Cancer |
| title_short | Co-administering Melatonin With an Estradiol-Progesterone Menopausal Hormone Therapy Represses Mammary Cancer Development in a Mouse Model of HER2-Positive Breast Cancer |
| title_sort | co administering melatonin with an estradiol progesterone menopausal hormone therapy represses mammary cancer development in a mouse model of her2 positive breast cancer |
| topic | breast cancer estradiol HER2/Neu melatonin menopausal hormone therapy metastasis |
| url | https://www.frontiersin.org/article/10.3389/fonc.2019.00525/full |
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