Progesterone generates cancer stem cells through membrane progesterone receptor-triggered signaling in basal-like human mammary cells

Varès, Guillaume; Sai, Sei; Wang, Bing; Fujimori, A.; Nenoi, Mitsuru; Nakajima, Tetsuo

doi:10.1016/j.canlet.2015.03.030

Cited by 33 publications

(26 citation statements)

References 63 publications

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“…In our current study we did not observe AKT phosphorylation with any of the progestins tested, including MPR-Ag in MCF10A cells (Figure 5). This is contrary to a recent report by Vares and colleagues, in which the authors report AKT stimulation in MCF10A cells with P4 and MPR-Ag (Vares et al, 2015). However, AKT activity was monitored by inversely correlating to FOXO transcriptional activity whereas direct evidence of pAKT activation was not shown.…”

Section: Discussioncontrasting

confidence: 99%

“…Recent studies provide evidence progestins can regulate AKT activation, potentially through MPRα (Zuo et al, 2010, Tan and Thomas, 2014, Vares, Sai, Wang et al, 2015), yet most results are based on indirect evidence. In Atlantic Croaker sperm, stimulation with endogenous progestin results in AKT activation, a function believed to be induced via MPRs activation (Tan and Thomas, 2014).…”

Section: Discussionmentioning

confidence: 99%

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Progestin-mediated activation of MAPK and AKT in nuclear progesterone receptor negative breast epithelial cells: The role of membrane progesterone receptors

Salazar

Lerma-Ortiz

Hooks

et al. 2016

Gene

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Progesterone (P4), a steroid produced during estrous cycles and gestation for maintenance of pregnancy, also plays key roles in breast development to allow lactation post-parturition. Progestins (P4 and related steroids) are also implicated in breast cancer etiology. Hormone replacement therapy containing both estrogen and progestins increases breast cancer incidence while estrogen hormone therapy lowers breast cancer risk. P4 signaling via nuclear P4 receptors (PRs) has been extensively studied in breast cancer, however, progestin signaling via non-classical membrane bound progestin receptors (MPRs and PGRMC1) remains unclear. Moreover, P4 metabolites and synthetic progestins may bind membrane progestin receptors. We hypothesized that PR-negative breast epithelial cells express non-classical progestin receptors, which activate intracellular signaling pathways differently depending on nature of progestin. Therefore, our objectives for the current study were to determine expression of MPRs and PGRMC1 in two PR-negative non-tumorigenic breast epithelial cell lines, assess progestin-mediated signaling and biological functions. We determined five MPR isoforms and PGRMC1 were present in MCF10A cells and all progestin receptors but MPRβ in MCF12A cells. MCF10A and MCF12A cells were treated with P4, select P4 metabolites (5αP and 3αHP), medroxyprogesterone acetate (MPA), or a specific MPRAgonist (MPR-Ag) and phosphorylation of ERK, p38, JNK, and AKT was characterized following treatment. To our knowledge this is the first report of ERK and JNK activation in MCF10A and MCF12A cells with P4, P4 metabolites, MPA, and MPR-Ag. Activation of ERK and JNK in cells treated with MPR-Ag implicates MPRs may serve as the receptors responsible for their activation. In contrast, p38 activation varied with cell type and with progestin treatment. P4 and MPA promoted AKT phosphorylation in the MCF12A cell line only whereas no activation was observed in MCF10A cells. Interestingly, cellular proliferation increased in MCF10A cells treated with MPA or 5αP, while MPR-Ag tended to slightly decrease proliferation. Collectively, our data highlights the importance of investigating the effects of synthetic progestins in breast cancer biology. Our results add to the understanding that various progestins have on breast epithelial cells and underscores the importance of considering both membrane bound receptors and progestin type in breast cancer development.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Progestin-mediated activation of MAPK and AKT in nuclear progesterone receptor negative breast epithelial cells: The role of membrane progesterone receptors

Salazar

Lerma-Ortiz

Hooks

et al. 2016

Gene

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“…The increase in breast cancer stem cells content was mediated by the PI3K/Akt signaling pathway via mPRs, which was associated with the downregulation of miR-29 and subsequent upregulation of KLF4 (a transcription factor required for cancer stem cells maintenance) (Vares et al, 2015).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

“…Furthermore, the recent finding that mPRs are also expressed in different cancer cells lines and tissues has opened a new interesting field of study. In fact, mPRs have been related to key processes in cancer disease such as proliferation, apoptosis, and metastasis (Dressing et al, 2012;Vares et al, 2015;Zuo et al, 2010).…”

Section: Introductionmentioning

confidence: 98%

Membrane progesterone receptors in reproduction and cancer

Valadez-Cosmes

Vázquez-Martínez

Cerbón

et al. 2016

Molecular and Cellular Endocrinology

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“…It also promotes proliferation of various cells [11]- [13]. Despite evidences showing protective and proliferative of progesterone on several cells, there are reports indicating that progesterone may have inhibiting role in cellular growth and proliferation [14]- [15]. The main …”

Section: Introductionmentioning

confidence: 99%

The Cytotoxic Effects of Progesterone on HEK cell line in Cell Culture

2016

2016 International Conference on Biological and Environmental Science (BIOES-16) June 8-9, 2016 New Jersey (USA)

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Progesterone generates cancer stem cells through membrane progesterone receptor-triggered signaling in basal-like human mammary cells

Cited by 33 publications

References 63 publications

Progestin-mediated activation of MAPK and AKT in nuclear progesterone receptor negative breast epithelial cells: The role of membrane progesterone receptors

Progestin-mediated activation of MAPK and AKT in nuclear progesterone receptor negative breast epithelial cells: The role of membrane progesterone receptors

Membrane progesterone receptors in reproduction and cancer

The Cytotoxic Effects of Progesterone on HEK cell line in Cell Culture

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