Mechanistic insights expatiating the biological role and regulatory implications of estrogen and HER2 in breast cancer metastasis

https://doi.org/10.1016/j.bbagen.2022.130113Get rights and content

Highlights

  • ER and HER2 provides prognostic and predictive implications in breast cancer.

  • Aberrant expression of ER and HER2 triggered events like EMT commencement, migration and metastasis.

  • Targeting small molecules using novel formulations provide recent advancement in managing BC metastasis.

Abstract

Breast cancer (BCa) has become the leading cause of death in women worldwide. Irrespective of advancement in cancer treatments, e.g., surgery, radiation, chemotherapy, hormonal therapy, immunotherapy, and targeted therapy, recurrence leading to metastasis poses the greatest threat in BCa management. BCa receptors estrogen (ER), progesterone (PR), and human epidermal growth factor receptor-2 (HER2) hold significant reputations as prognostic and predictive biomarkers in therapeutic decision-making. Under normal physiological conditions, these receptors modulate critical biological functions, e.g., cell migration, proliferation, and apoptosis events, etc. However, aberrant expression causes deviations, triggering signaling course to adapt permanent switching “ON” mode. The later events induce rapid and unrestrained proliferation leading to cancer. As conventional ways of cancer management ultimately lead to resistance; therefore, recently targeted therapies have been extensively studied to conquer resistance. Targeting various small molecules in downstream signaling has become an area of interest in scientific society. The severity of cancer converts many folds soon after it takes on a migratory approach that eventually commences metastasis. Cancer migration comprises protrusion of cytoplasm at the leading edge of the migration forward-facing, establishing adhesions with the basic cell-matrix, disassembly of the adhesions at the back end of the cell, and actin-myosin fiber contractions to pull the bulk of the cytoplasm forward. On the other hand, metastatic progression comprises a cascade of events, including invasion, migration, and establishment of tumor microenvironment. The progression of BCa from early stage to metastatic development causes remarkable heterogeneity. Interference at any explicit level could hamper the process, and it has thus become an area of interest for scientists. Metastasis is the ultimate cause of spreading tumor cells to invade distant organs. Recently small molecule inhibitors of protein tyrosine kinases, which can cross the blood-brain barrier, have become a center point of research for investigators in developing novel treatment strategies against BCa management.

Section snippets

Background

Breast cancer (BCa) has become the most prevalent malignancy and prime cause of metastatic deaths in women worldwide, conferring to the reports of GLOBOCAN 2020 [1]. According to the data, the global cancer burden has mounted to 19.2 million new cases identified in 2020 and 9.95 million cancer deaths in 2020. While talking about BCa, it has risen to 2.26 million new cases worldwide and 0.68 million deaths in 2020, as shown in (Fig. 1) [1]. Even with the advancement in treatments available to

Prognostic and predictive markers for ER and HER2

The statistics recognized at the time of diagnosis, which compares the clinical results independent of adjuvant therapy, are viewed as prognostic indicators. Whereas statistical values after the therapy course indicate the magnitude of response are regarded as predictive markers or predictive indicators [17]. Understanding this description clarifies that some markers can be prognostic and predictive indicators. Conventional morphological findings such as lymphovascular invasion, size and grade

Biological functions of ER and HER2 in BCa migration

The capability of a neoplastic cell to endure migration and invasion permits it to transform and positioned inside the tissues [29]. For instance, these courses permit cancer cells to go in lymphatic and blood vessels for distribution into the circulation and then endure metastatic development in distant organs. To blowout within the tissues, neoplastic cells opt for comparable migration procedures, if not alike, to those that ensue in regular, non-cancer cells throughout physiological courses,

Tumor metastasis

The metastasis of tumor cells from their original location to distant organs is responsible for innumerable mortalies due to cancer [68]. The molecular mechanism for cancer spreading is still not yet well known. For cancer proliferation and metastasis, the main requirement is the ability of the cancer cell to migrate and penetrate surrounding tissues; therefore, the focus is now shifted towards pinpointing the contributing small molecules in cell motility, migration, and invasion. The targeted

Novel strategy of targeting small molecules

The small molecules protein tyrosine kinase is of great interest in cancer management as they yield enhanced activity in cancerous cells [131]. There is a direct correlation between poor prognosis and subsequent shorter survival rates in ovarian and BCa patients and increased expression of protein kinase receptors [135]. Numerous EGFR tyrosine kinase inhibitors are being probed in BCa from both natural and synthetic origins [[136], [137], [138], [139], [140], [141], [142]]. The fundamental

Conclusions

Although metastatic BCa is a fatal phenomenon, the progress in understanding the etiology of the disease is now being transformed into the treatment protocol. The BCa receptors ER, PR, and HER2 play a prognostic role and are also the predictive markers for disease progression. These receptors play various biological functions, and deviation from the normal growth leads to disruption in the balance of their biological role. In the advanced stage, the BCa metastasizes and migrates to distant

Availability of data and materials

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Ethics approval

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Consent to participate

Not applicable.

Consent of publication

Not applicable.

Author contributions

Conceptualization, Mohsin Ahmad Ghauri; Data analysis and Writing—Original Draft Preparation, Mohsin Ahmad Ghauri, Ali Raza, Uzma Hayat; Editing, Hafiz M.N. Iqbal and Muhammad Bilal; Revisions, Final editing, Project & Grant acquisition, Hafiz M.N. Iqbal and Muhammad Bilal.

Declaration of Competing Interest

Not applicable.

Acknowledgment

We are grateful to the National Natural Science Foundation of China. This project is supported by the National Natural Science Foundation of China 31700546.

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