Skip to main content

Advertisement

SpringerLink
Log in

Breast Cancer Invasion and Metastasis by mPRα Through the PI3K/Akt Signaling Pathway

  • Original Article
  • Published:
Pathology & Oncology Research

Abstract

Invasive breast cancer is the most common type of malignancy in women worldwide. However, the mechanism responsible for breast cancer metastasis is still unclear and needs further illustration. It has been proven that matrix metallopeptidase 9 (MMP-9) promotes metastasis of the cancer cells. However, the interaction between mPRα and MMP-9 has not been studied. Therefore, in the present research, the effect of MMP-9 on the malignant progression of invasive breast cancer promoted by membrane progesterone receptorα (mPRα) was investigated. The results showed that the protein expression of mPRα, p-Akt and MMP-9 increased in the cancerous tissues compared to that of the noncancerous breast tissue. Furthermore, a positive correlation was found between mPRα and C-erbB-2, as well as the number of involved local lymph nodes. On the other hand, a negative correlation was observed between mPRα and estrogen receptors (ER) along with progesterone receptors (PR). Similarly, a positive association was found between MMP-9 and the number of involved local lymph nodes. Besides, the high expression of MMP-9 also had a positive correlation with the tumor size. However, the high level of MMP-9 had a negative correlation with ER and PR. In addition, there was a positive correlation between mPRα and p-Akt together with MMP-9. The results confirm that mPRα was a major marker of harmful prognosis and it promoted the expression of MMP-9 during invasion to the local lymph nodes through the pathway of PI3K/Akt. The present study provided a novel therapeutic strategy to inhibit breast cancer growth by preventing mPRα signaling pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Chambers AF, Naumov GN, Varghese HJ, Nadkarni KV, MacDonald IC, Groom AC (2001) Critical steps in hematogenous metastasis: an overview. Surg Oncol Clin N Am 10(2):243–255 vii

    CAS  PubMed  Google Scholar 

  2. Basu A, Rowan BG (2005) Genes related to estrogen action in reproduction and breast cancer. Front Biosci : J Virtual Libr 10:2346–2372

    Article  CAS  Google Scholar 

  3. Carnevale RP, Proietti CJ, Salatino M, Urtreger A, Peluffo G, Edwards DP, et al. (2007) Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways. Mol Endocrinol 21(6):1335–1358. doi:10.1210/me.2006-0304

    Article  CAS  PubMed  Google Scholar 

  4. Karteris E, Zervou S, Pang Y, Dong J, Hillhouse EW, Randeva HS, et al. (2006) Progesterone signaling in human myometrium through two novel membrane G protein-coupled receptors: potential role in functional progesterone withdrawal at term. Mol Endocrinol 20(7):1519–1534. doi:10.1210/me.2005-0243

    Article  CAS  PubMed  Google Scholar 

  5. Dressing GE, Alyea R, Pang Y, Thomas P (2012) Membrane progesterone receptors (mPRs) mediate progestin induced antimorbidity in breast cancer cells and are expressed in human breast tumors. Horm Cancer 3(3):101–112. doi:10.1007/s12672-012-0106-x

    Article  CAS  PubMed  Google Scholar 

  6. Alizadeh AA, Ross DT, Perou CM, van de Rijn M (2001) Towards a novel classification of human malignancies based on gene expression patterns. J Pathol 195(1):41–52. doi:10.1002/path.889

    Article  CAS  PubMed  Google Scholar 

  7. Loya A, Guray M, Hennessy BT, Middleton LP, Buchholz TA, Valero V, et al. (2009) Prognostic significance of occult axillary lymph node metastases after chemotherapy-induced pathologic complete response of cytologically proven axillary lymph node metastases from breast cancer. Cancer 115(8):1605–1612. doi:10.1002/cncr.24173

    Article  PubMed  Google Scholar 

  8. Illemann M, Bird N, Majeed A, Sehested M, Laerum OD, Lund LR, et al. (2006) MMP-9 is differentially expressed in primary human colorectal adenocarcinomas and their metastases. Mol Cancer Res : MCR 4(5):293–302. doi:10.1158/1541-7786.MCR-06-0003

    Article  CAS  PubMed  Google Scholar 

  9. Gompel A (2012) Micronized progesterone and its impact on the endometrium and breast vs. progestogens. Climacteric : J Int Menopause Soc 15(Suppl 1):18–25. doi:10.3109/13697137.2012.669584

    Article  CAS  Google Scholar 

  10. L’Hermite M (2013) HRT optimization, using transdermal estradiol plus micronized progesterone, a safer HRT. Climacteric : J Int Menopause Soc. 16(Suppl 1):44–53. doi:10.3109/13697137.2013.808563

    Article  Google Scholar 

  11. Kuhl H, Schneider HP (2013) Progesterone–promoter or inhibitor of breast cancer. Climacteric : J Int Menopause Soc 16(Suppl 1):54–68. doi:10.3109/13697137.2013.768806

    Article  CAS  Google Scholar 

  12. Zhu Y, Rice CD, Pang Y, Pace M, Thomas P (2003) Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proc Natl Acad Sci U S A 100(5):2231–2236. doi:10.1073/pnas.0336132100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhu Y, Bond J, Thomas P (2003) Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc Natl Acad Sci U S A 100(5):2237–2242. doi:10.1073/pnas.0436133100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Thomas P, Pang Y, Dong J, Groenen P, Kelder J, de Vlieg J, et al. (2007) Steroid and G protein binding characteristics of the seatrout and human progestin membrane receptor alpha subtypes and their evolutionary origins. Endocrinology 148(2):705–718. doi:10.1210/en.2006-0974

    Article  CAS  PubMed  Google Scholar 

  15. Lyons TJ, Villa NY, Regalla LM, Kupchak BR, Vagstad A, Eide DJ (2004) Metalloregulation of yeast membrane steroid receptor homologs. Proc Natl Acad Sci U S A 101(15):5506–5511. doi:10.1073/pnas.0306324101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. van Beijnum JR, Petersen K, Griffioen AW (2009) Tumor endothelium is characterized by a matrix remodeling signature. Front Biosci. 1:216–225

    Article  Google Scholar 

  17. Youssef NS, Hakim SA (2014) Association of fascin and matrix metalloproteinase-9 expression with poor prognostic parameters in breast carcinoma of egyptian women. Diagn Pathol. 9:136. doi:10.1186/1746-1596-9-136

    Article  PubMed  PubMed Central  Google Scholar 

  18. Xue B, Huang W, Yuan X, Xu B, Lou Y, Zhou Q, et al. (2015) YSY01A, a novel proteasome inhibitor, induces cell cycle arrest on G2 phase in MCF-7 cells via ERalpha and PI3K/Akt pathways. J Cancer 6(4):319–326. doi:10.7150/jca.10733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nagaraj G, Ma C (2015) Revisiting the estrogen receptor pathway and its role in endocrine therapy for postmenopausal women with estrogen receptor-positive metastatic breast cancer. Breast Cancer Res Treat. doi:10.1007/s10549-015-3316-4

    PubMed  Google Scholar 

  20. Paez J, Sellers WR (2003) PI3K/PTEN/AKT pathway. A critical mediator of oncogenic signaling. Cancer Treat Res 115:145–167

    Article  CAS  PubMed  Google Scholar 

  21. Pu P, Kang C, Li J, Jiang H (2004) Antisense and dominant-negative AKT2 cDNA inhibits glioma cell invasion. Tumour Biol : J Int Soc Oncodevelopmental Biol Med 25(4):172–178. doi:10.1159/000081099

    Article  CAS  Google Scholar 

Download references

Authors’ Contributions

Zhishuang Li and ChunyanZhang carried out the tissue microarray. Limin Sun and Yan Wang carried out the immunohistochemistry. Xiaojuan Wu, Peng Su and Xiaowang participated in the design of the study and performed the statistical analysis. Rong Ma and Peng Gao conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

Author information

Authors and Affiliations

  1. Department of Pathology, School of Medicine, Shandong Univeristy, 44 Wenhuaxi Road, Jinan, Shandong, 250012, China

    Xiaojuan Wu, Xiao Wang, Peng Su, Zhishuang Li, Chunyan Zhang, Yan Wang & Peng Gao

  2. Department of Orthopedics, Shandong Jiaotong Hospital, Shandong, China

    Limin Sun

  3. Department of Breast Surgery, QiLu Hospital, Shandong University, Shandong, China

    Rong Ma

Authors
  1. Xiaojuan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Limin Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peng Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhishuang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chunyan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peng Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rong Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Peng Gao or Rong Ma.

Ethics declarations

The procedures in this study were in accordance with the ethical standards of the responsible committee of the Shandong University on human experimentation.

Conflict of Interest

The experiments abide by the current laws of China and there were no conflict of interest among the authors.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81402181).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, X., Sun, L., Wang, X. et al. Breast Cancer Invasion and Metastasis by mPRα Through the PI3K/Akt Signaling Pathway. Pathol. Oncol. Res. 22, 471–476 (2016). https://doi.org/10.1007/s12253-015-0023-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-015-0023-8

Keywords

Search

Navigation