Progesterone suppresses the invasion and migration of breast cancer cells irrespective of their progesterone receptor status - a short report

Godbole, Mukul; Tiwary, Kanishka; Badwe, Rajendra; Gupta, Sudeep; Dutt, Amit

doi:10.1007/s13402-017-0330-z

Cited by 23 publications

(37 citation statements)

References 27 publications

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“…We recently showed that progesterone decreases the activation of multiple kinases like EGFR, AKT1 and ERK1/2 in breast cancer cells, leading to suppression of cell migration (19). To test, if NDRG1 mediate inactivation of EGFR/AKT1/ERK1/2 kinases in response to progesterone, we knocked down the expression of NDRG1 in T47D and MDA-MB-231 cells (Figure 10A and 11A).…”

Section: Resultsmentioning

confidence: 99%

“…Cells were tested for mycoplasma and were made mycoplasma-free using EZKill Mycoplasma Removal reagent (HiMedia). T47D, BT474, MDA-MB-231, MCF7 and ZR-75-1 cells were cultured as described previously (19,36). The immortalized normal-like 184A1 cell line was cultured in DMEM:F12 medium (HiMedia) supplemented with 28.18IU Insulin, 20ng/ml EGF and 500ng/ml Hydrocortisone.…”

Section: Methodsmentioning

confidence: 99%

“…Gene expression studies probing the targets of progesterone have either been performed restrictively in PR-positive breast cancer cell lines or in the presence of other hormones (14–18). Although few studies suggest a beneficial effect of progesterone, progesterone-responsive genes in PR-negative cells have not been studied (14,15,17,19). In order to identify targets of progesterone independent of PR status of cells, we set to perform an integrated genomic profiling of a panel of PR-positive and PR-negative breast cancer cell lines treated with progesterone, followed by functional analysis of the components found to be significantly altered.…”

Section: Introductionmentioning

confidence: 99%

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Up-regulation of the kinase gene SGK1 by progesterone activates the AP-1–NDRG1 axis in both PR-positive and -negative breast cancer cells

Godbole

Togar

Patel

et al. 2018

Journal of Biological Chemistry

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Preoperative progesterone intervention has been shown to confer a survival benefit to breast cancer patients independently of their progesterone receptor (PR) status. This observation raises the question how progesterone affects the outcome of PR-negative cancer. Here, using microarray and RNA-Seq–based gene expression profiling and ChIP-Seq analyses of breast cancer cells, we observed that the serum- and glucocorticoid-regulated kinase gene (SGK1) and the tumor metastasis–suppressor gene N-Myc downstream regulated gene 1 (NDRG1) are up-regulated and that the microRNAs miR-29a and miR-101-1 targeting the 3’UTR region of SGK1 are down-regulated in response to progesterone. We further demonstrate a dual-phase transcriptional and posttranscriptional regulation of SGK1 in response to progesterone, leading to an up-regulation of NDRG1 that is mediated by a set of genes regulated by the transcription factor AP-1. We found that NDRG1, in turn, inactivates a set of kinases impeding the invasion and migration of breast cancer cells. In summary, we propose a model for the mode of action of progesterone in breast cancer. This model helps decipher the molecular basis of observations in a randomized clinical trial of the effect of progesterone on breast cancer and has therefore the potential to improve the prognosis of breast cancer patients receiving preoperative progesterone treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Up-regulation of the kinase gene SGK1 by progesterone activates the AP-1–NDRG1 axis in both PR-positive and -negative breast cancer cells

Godbole

Togar

Patel

et al. 2018

Journal of Biological Chemistry

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“…The average pixel density of the duplicate spots for each of the kinases was subtracted from the negative density and was plotted, as detailed earlier. 35…”

Section: Receptor Tyrosine Kinase Proteome Arraymentioning

confidence: 99%

ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer

Iyer

Shrikhande

Ranjan

et al. 2018

Intl Journal of Cancer

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The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. Our integrated analysis of whole exome sequencing, copy number alterations, immunohistochemical, and phospho-proteome array profiling indicates ERBB2 alterations in 40% early-stage rare gallbladder tumors, among an ethnically distinct population not studied before, that occurs through overexpression in 24% (n=25) and recurrent mutations in 14% tumors (n=44); along with co-occurring KRAS mutation in 7% tumors (n=44). We demonstrate that ERBB2 heterodimerize with EGFR to constitutively activate the ErbB signaling pathway in gallbladder cells. Consistent with this, treatment with ERBB2-specific, EGFR-specific shRNA or with a covalent EGFR family inhibitor Afatninb inhibits tumor-associated characteristics of the gallbladder cancer cells. Furthermore, we observe an in vivo reduction in tumor size of gallbladder xenografts in response to Afatinib is paralleled by a reduction in the amounts of phospho-ERK, in tumors harboring KRAS (G13D) mutation but not in KRAS (G12V) mutation, supporting an essential role of the ErbB pathway. In overall, besides implicating ERBB2 as an important therapeutic target under neo-adjuvant or adjuvant settings, we present the first evidence that the presence of KRAS mutations may preclude gallbladder cancer patients to respond to anti-EGFR treatment, similar to a clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer.

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“…The Pixel density of each spot in the array in duplicate was quantified using Image J macro-Protein array analyzer plug in. The average pixel density of the duplicate spots for each of the kinases was subtracted from the negative density and was plotted, as detailed earlier (Godbole et al, 2017).…”

Section: Receptor Tyrosine Kinase Proteome Arraymentioning

confidence: 99%

ERBB2andKRASAlterations Mediate Response to EGFR Inhibitors in early stage Gallbladder Cancer

Iyer

Shrikhande

Ranjan

et al. 2018

Preprint

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The uncommonness of gallbladder cancer has contributed to the generally poor understanding of the disease, with scant reports restricted to advance-stage tumors. Here, using an integrated analysis of whole exome and phospho-proteome, we show recurrent activating ERBB2 and KRAS somatic mutations are present in 6 and 3 of 44 early-stage rare gallbladder tumors, respectively. In vitro and in vivo cell-based and biochemical assays reveal an essential role of ErbB pathway activation for the survival of gallbladder cells. Interestingly, the genetic and pharmacological dependencies of gallbladder cells are dependent on the KRAS mutant allele status, reminiscent of the clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer. In overall, we present the first evidence that the presence of KRAS (G12V), but not KRAS (G13D) mutation, may preclude gallbladder cancer patients to respond to anti-EGFR treatment, leading to an early adoption of an approved treatment regimen for gallbladder cancer patients.

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Progesterone suppresses the invasion and migration of breast cancer cells irrespective of their progesterone receptor status - a short report

Cited by 23 publications

References 27 publications

Up-regulation of the kinase gene SGK1 by progesterone activates the AP-1–NDRG1 axis in both PR-positive and -negative breast cancer cells

Up-regulation of the kinase gene SGK1 by progesterone activates the AP-1–NDRG1 axis in both PR-positive and -negative breast cancer cells

ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer

ERBB2andKRASAlterations Mediate Response to EGFR Inhibitors in early stage Gallbladder Cancer

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