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Breast Cancer Research: Rapid Progress and Innovation

13 August 2025

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The field of breast cancer research is advancing rapidly, with increasingly refined subtype classifications, complex signalling pathways, and innovative treatment approaches. Whether considering endocrine therapy for luminal breast cancer, targeted therapies for HER2-overexpressing subtypes, or chemotherapy explorations for triple-negative breast cancer, these developments continuously bring new hope to patients. The following provides cutting-edge information on breast cancer, offering in-depth knowledge to support advances in precision medicine.

I. Molecular Subtypes and Classification [1]

Breast cancer is a major global health concern, with an estimated 2.31 million new cases and over 665,000 deaths reported in 2022, ranking first among all cancers in both incidence and mortality. Screening programs play a critical role in reducing the disease burden by enabling early detection and timely diagnosis, which in turn lowers both incidence and mortality.

Clinically, breast cancer classification relies on detecting hormone receptors (HR), including estrogen receptor (ER) and progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 through immunohistochemistry or in situ hybridization, identifying four clinical subtypes:

· Luminal A
· Luminal B
· ErbB2/HER2-positive

Figure 1. Intrinsic Molecular Subtypes of Breast Cancer. [2]

Each subtype exhibits distinct clinical symptoms, phenotypes, and treatment sensitivities, which guide therapeutic decisions and influence prognosis [3,4].

· Luminal A includes tumours that are estrogen receptor (ER) positive and progesterone receptor (PR) positive but HER2 negative. These tumour cells grow slowly, have a favourable prognosis, and respond well to hormone therapy.
· Luminal B includes tumours that are ER positive, PR negative, and either HER2+ or HER2−. They have higher Ki67 levels, indicating faster cell growth, and can be treated with hormone therapy and chemotherapy.
· ErbB2/HER2-positive breast cancer includes tumours that are ER/PR negative but ErbB2/HER2 positive and show ErbB2 gene amplification. They have a relatively poor prognosis, are unresponsive to endocrine therapy, but can be treated with targeted therapies.
· Basal-like breast cancer is typically ER/PR/HER2 negative and shows significant expression of CK5/6.
· Triple-negative breast cancer (TNBC) is a major subclass of basal-like breast cancer (approximately 70%) and is one of the most aggressive forms of breast cancer, with higher recurrence risk and poor prognosis.

II. Signaling Pathways [5]

Breast cancer is a heterogeneous disease characterized by multiple subtypes. The development and progression of breast cancer result from the influence of subtype-specific and shared signaling pathways and their intricate crosstalk. Targeting these key signaling pathways can improve breast cancer prognosis. The most important pathways recognized in breast cancer include:
1. Estrogen Receptor (ER) Pathway
2. HER2 Signaling Pathway
3. PI3K/AKT/mTOR Pathway
4. MAPK Pathway
5. Cyclin D1/CDK4/6/RB1 Pathway

Figure 2. Key Signalling Pathways in Breast Cancer. [5]

(i) Estrogen Receptor Pathway

· The two main steroid hormones associated with breast cancer are estrogen and progesterone, which are involved in the growth and proliferation of breast cells.
· Estrogen is considered the primary initiator of breast cancer, particularly in ER-positive breast cancer subtypes.
· The most common type of human estrogen is 17β-estradiol (E2). E2 binding to the estrogen receptor (ER, primarily ERα, encoded by the ESR1 gene) stimulates the classical genomic ER signalling pathway, ultimately contributing to breast cancer cell proliferation and reduced apoptosis.

(ii) HER2 Signalling Pathway

· HER2 is encoded by the ERBB2 gene and is one of four members of the epidermal growth factor receptor (EGFR) family, which includes EGFR (HER1), HER2, HER3, and HER4. HER2 is enriched in approximately 15-20% of breast cancers, which is associated with a highly aggressive phenotype and poor prognosis.
· In breast cancer, activation of HER2 signalling further triggers various downstream signalling pathways, such as PI3K/AKT, MAPK, and JAK/STAT signalling pathways, all of which lead to cancer cell proliferation, survival, adhesion, and metastasis.
· Targeting HER2 has proven highly efficacious in treating HER2-positive breast cancer patients, profoundly benefiting their overall survival.

(iii) PI3K/AKT/mTOR Pathway

· Phosphatidylinositol 3-kinase (PI3K) is a group of intracellular kinases divided into three classes (I, II, and III). Among them, Class I PI3Ks, composed of regulatory (p85) and catalytic (p110) subunits, are the most extensively studied.
· Mutations commonly occur in the p110α subunit (encoded by PIK3CA) across all breast cancer subtypes, but mutation frequencies are particularly high in ER-positive breast cancer. PIK3CA mutations are observed in approximately 40% of ER-positive breast cancers, 25% of HER2-positive breast cancers, and 9% of TNBCs.
· PIK3CA mutations lead to PI3K activation, thereby activating downstream AKT and mTOR targets.

(iv) Cyclin D1/CDK4/6/RB1 Pathway

· In breast cancer, the cyclin D1/CDK4/6/RB1 complex plays a crucial role in ER signalling-mediated cell proliferation.
· Specifically, the presence of estrogen in ER-positive breast cancer induces the expression of cyclin D1 (encoded by CCDN1), thereby activating CDK4/6. CDK4/6 activity leads to hyperphosphorylation of RB1, promoting cell cycle progression and cellular proliferation.
· Additionally, increased MAPK and PI3K/AKT pathways can also drive CCDN1 transcription, ultimately activating the cyclin D1/CDK4/6/RB1 pathway.

Figure 3. Oncogenic Signalling Pathways in HR+/HER2- Advanced Breast Cancer and Potential Therapeutic Strategies. [6]

III. Systemic Therapies [4]

The biological and clinical characteristics of different breast cancer subtypes vary significantly, giving rise to different subtype-specific treatment approaches and clinical applications.

In HR+/HER2− breast cancer, aromatase inhibitors (AIs) are the conventional regimen for inhibiting estrogen synthesis. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) have ushered in a new era of endocrine therapy for HR+/HER2− breast cancer. Cyclin-dependent kinase (CDK) 4/6 inhibitors represent another novel therapeutic strategy for HR+/HER2− breast cancer.

Additionally, inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway has shown promising clinical efficacy.

In HER2+ breast cancer, dual HER2-targeted therapy with trastuzumab and pertuzumab has been established as the standard of care. Following the failure of conventional anti-HER2 therapies, the introduction of tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs) continues to extend patients' clinical prognosis through different mechanisms of action.

For triple-negative breast cancer (TNBC), chemotherapy has long been a classic and effective treatment approach. In recent years, translational medicine advances have expanded treatment options with the introduction of poly(ADP-ribose) polymerase inhibitors (PARPi) and anti-trophoblast cell surface antigen 2 (Trop2) ADCs.

Figure 4. Systemic Therapies for Breast Cancer. [4]

Summary

· Endocrine therapy is particularly effective for HR+/HER2- breast cancer
· HER2-targeted therapies benefit HER2+ breast cancer patients
· TNBC: Most aggressive and heterogeneous, with chemotherapy as the standard treatment approach
· Other therapies: Immunotherapy, antibody-drug conjugates, and poly(ADP-ribose) polymerase inhibitors (PARPi) [7]

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At AmBeed Life Science, we offer an Anti-Breast Cancer Compound Library that contains over 1,600 small-molecule compounds targeting PD-1/PD-L1, Aromatase, ERR, STAT3, HER2, EGFR, and other targets for combination therapy in breast cancer treatment, suitable for high-throughput screening and high-content screening.

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References

[1]Cell Rep Med. 2024;5(9):101719.

[2]NPJ Breast Cancer. 2022;8(1):95.

[3]Oncogene. 2024;43(23):1727-1741.

[4]Signal Transduct Target Ther. 2025;10(1):49.

[5]Signal Transduct Target Ther. 2024;9(1):83.

[6]NPJ Breast Cancer. 2023;9(1):74.

[7]Cell Rep Med. 2024;5(9):101719.

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